Human genes and gene expression products V

ABSTRACT

This invention relates to novel human polynucleotides and variants thereof, their encoded polypeptides and variants thereof, to genes corresponding to these polynucleotides and to proteins expressed by the genes. The invention also relates to diagnostic and therapeutic agents employing such novel human polynucleotides, their corresponding genes or gene products, e.g., these genes and proteins, including probes, antisense constructs, and antibodies.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. provisional patent application Ser. No. 60/085,426, filed May 14, 1998; and of U.S. provisional patent application Ser. No. 60/085,537, filed May 15, 1998; and of U.S. provisional patent application Ser. No. 60/085,696, filed May 15, 1998; and of U.S. provisional patent application Ser. No. 60/105,234, filed Oct. 21, 1998; and of U.S. provisional patent application Ser. No. 60/105,877 filed Oct. 27, 1998; each of which applications are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to polynucleotides of human origin and the encoded gene products.

BACKGROUND OF THE INVENTION

Identification of novel polynucleotides, particularly those that encode an expressed gene product, is important in the advancement of drug discovery, diagnostic technologies, and the understanding of the progression and nature of complex diseases such as cancer. Identification of genes expressed in different cell types isolated from sources that differ in disease state or stage, developmental stage, exposure to various environmental factors, the tissue of origin, the species from which the tissue was isolated, and the like is key to identifying the genetic factors that are responsible for the phenotypes associated with these various differences.

This invention provides novel human polynucleotides, the polypeptides encoded by these polynucleotides, and the genes and proteins corresponding to these novel polynucleotides.

SUMMARY OF THE INVENTION

This invention relates to novel human polynucleotides and variants thereof, their encoded polypeptides and variants thereof, to genes corresponding to these polynucleotides and to proteins expressed by the genes. The invention also relates to diagnostics and therapeutics comprising such novel human polynucleotides, their corresponding genes or gene products, including probes, antisense nucleotides, and antibodies. The polynucleotides of the invention correspond to a polynucleotide comprising the sequence information of at least one of SEQ ID NOS:1–2707.

Various aspects and embodiments of the invention will be readily apparent to the ordinarily skilled artisan upon reading the description provided herein.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to polynucleotides comprising the disclosed nucleotide sequences, to full length cDNA, mRNA genomic sequences, and genes corresponding to these sequences and degenerate variants thereof, and to polypeptides encoded by the polynucleotides of the invention and polypeptide variants. The following detailed description describes the polynucleotide compositions encompassed by the invention, methods for obtaining cDNA or genomic DNA encoding a full-length gene product, expression of these polynucleotides and genes, identification of structural motifs of the polynucleotides and genes, identification of the function of a gene product encoded by a gene corresponding to a polynucleotide of the invention, use of the provided polynucleotides as probes and in mapping and in tissue profiling, use of the corresponding polypeptides and other gene products to raise antibodies, and use of the polynucleotides and their encoded gene products for therapeutic and diagnostic purposes.

Polynucleotide Compositions

The scope of the invention with respect to polynucleotide compositions includes, but is not necessarily limited to, polynucleotides having a sequence set forth in any one of SEQ ID NOS:1–2707; polynucleotides obtained from the biological materials described herein or other biological sources (particularly human sources) by hybridization under stringent conditions (particularly conditions of high stringency); genes corresponding to the provided polynucleotides; variants of the provided polynucleotides and their corresponding genes, particularly those variants that retain a biological activity of the encoded gene product (e.g., a biological activity ascribed to a gene product corresponding to the provided polynucleotides as a result of the assignment of the gene product to a protein family(ies) and/or identification of a functional domain present in the gene product). Other nucleic acid compositions contemplated by and within the scope of the present invention will be readily apparent to one of ordinary skill in the art when provided with the disclosure here. “Polynucleotide” and “nucleic acid” as used herein with reference to nucleic acids of the composition is not intended to be limiting as to the length or structure of the nucleic acid unless specifically indicted.

The invention features polynucleotides that are expressed in human tissue, specifically human colon, breast, and/or lung tissue. Novel nucleic acid compositions of the invention of particular interest comprise a sequence set forth in any one of SEQ ID NOS:1–2707 or an identifying sequence thereof. An “identifying sequence” is a contiguous sequence of residues at least about 10 nt to about 20 nt in length, usually at least about 50 nt to about 100 nt in length, that uniquely identifies a polynucleotide sequence, e.g., exhibits less than 90%, usually less than about 80% to about 85% sequence identity to any contiguous nucleotide sequence of more than about 20 nt. Thus, the subject novel nucleic acid compositions include full length cDNAs or mRNAs that encompass an identifying sequence of contiguous nucleotides from any one of SEQ ID NOS: 1–2707.

The polynucleotides of the invention also include polynucleotides having sequence similarity or sequence identity. Nucleic acids having sequence similarity are detected by hybridization under low stringency conditions, for example, at 50° C. and 10×SSC (0.9 M saline/0.09 M sodium citrate) and remain bound when subjected to washing at 55° C. in 1×SSC. Sequence identity can be determined by hybridization under stringent conditions, for example, at 50° C. or higher and 0.1×SSC (9 mM saline/0.9 mM sodium citrate). Hybridization methods and conditions are well known in the art, see, e.g., U.S. Pat. No. 5,707,829. Nucleic acids that are substantially identical to the provided polynucleotide sequences, e.g. allelic variants, genetically altered versions of the gene, etc., bind to the provided polynucleotide sequences (SEQ ID NOS:1–2707) under stringent hybridization conditions. By using probes, particularly labeled probes of DNA sequences, one can isolate homologous or related genes. The source of homologous genes can be any species, e.g. primate species, particularly human; rodents, such as rats and mice; canines, felines, bovines, ovines, equines, yeast, nematodes, etc.

Preferably, hybridization is performed using at least 15 contiguous nucleotides (nt) of at least one of SEQ ID NOS:1–2707. That is, when at least 15 contiguous nt of one of the disclosed SEQ ID NOS. is used as a probe, the probe will preferentially hybridize with a nucleic acid comprising the complementary sequence, allowing the identification and retrieval of the nucleic acids that uniquely hybridize to the selected probe. Probes from more than one SEQ ID NO. can hybridize with the same nucleic acid if the cDNA from which they were derived corresponds to one mRNA. Probes of more than 15 nt can be used, e.g., probes of from about 18 nt to about 100 nt, but 15 nt represents sufficient sequence for unique identification.

The polynucleotides of the invention also include naturally occurring variants of the nucleotide sequences (e.g., degenerate variants, allelic variants, etc.). Variants of the polynucleotides of the invention are identified by hybridization of putative variants with nucleotide sequences disclosed herein, preferably by hybridization under stringent conditions. For example, by using appropriate wash conditions, variants of the polynucleotides of the invention can be identified where the allelic variant exhibits at most about 25–30% base pair (bp) mismatches relative to the selected polynucleotide probe. In general, allelic variants contain 15–25% bp mismatches, and can contain as little as even 5–15%, or 2–5%, or 1–2% bp mismatches, as well as a single bp mismatch.

The invention also encompasses homologs corresponding to the polynucleotides of SEQ ID NOS:1–2707, where the source of homologous genes can be any mammalian species, e.g., primate species, particularly human; rodents, such as rats; canines, felines, bovines, ovines, equines, yeast, nematodes, etc. Between mammalian species, e.g., human and mouse, homologs generally have substantial sequence similarity, e.g., at least 75% sequence identity, usually at least 90%, more usually at least 95% between nucleotide sequences. Sequence similarity is calculated based on a reference sequence, which may be a subset of a larger sequence, such as a conserved motif, coding region, flanking region, etc. A reference sequence will usually be at least about 18 contiguous nt long, more usually at least about 30 nt long, and may extend to the complete sequence that is being compared. Algorithms for sequence analysis are known in the art, such as gapped BLAST, described in Altschul, et al. Nucleic Acids Res. (1997) 25:3389–3402.

In general, variants of the invention have a sequence identity greater than at least about 65%, preferably at least about 75%, more preferably at least about 85%, and can be greater than at least about 90% or more as determined by the Smith-Waterman homology search algorithm as implemented in MPSRCH program (Oxford Molecular). For the purposes of this invention, a preferred method of calculating percent identity is the Smith-Waterman algorithm, using the following. Global DNA sequence identity must be greater than 65% as determined by the Smith-Waterman homology search algorithm as implemented in MPSRCH program (Oxford Molecular) using an affine gap search with the following search parameters: gap open penalty, 12; and gap extension penalty, 1.

The subject nucleic acids can be cDNAs or genomic DNAs, as well as fragments thereof, particularly fragments that encode a biologically active gene product and/or are useful in the methods disclosed herein (e.g., in diagnosis, as a unique identifier of a differentially expressed gene of interest, etc.). The term “cDNA” as used herein is intended to include all nucleic acids that share the arrangement of sequence elements found in native mature mRNA species, where sequence elements are exons and 3′ and 5′ non-coding regions. Normally mRNA species have contiguous exons, with the intervening introns, when present, being removed by nuclear RNA splicing, to create a continuous open reading frame encoding a polypeptide of the invention.

A genomic sequence of interest comprises the nucleic acid present between the initiation codon and the stop codon, as defined in the listed sequences, including all of the introns that are normally present in a native chromosome. It can further include the 3′ and 5′ untranslated regions found in the mature mRNA. It can further include specific transcriptional and translational regulatory sequences, such as promoters, enhancers, etc., including about 1 kb, but possibly more, of flanking genomic DNA at either the 5′ and 3′ end of the transcribed region. The genomic DNA can be isolated as a fragment of 100 kbp or smaller; and substantially free of flanking chromosomal sequence. The genomic DNA flanking the coding region, either 3′ and 5′, or internal regulatory sequences as sometimes found in introns, contains sequences required for proper tissue, stage-specific, or disease-state specific expression.

The nucleic acid compositions of the subject invention can encode all or a part of the subject polypeptides. Double or single stranded fragments can be obtained from the DNA sequence by chemically synthesizing oligonucleotides in accordance with conventional methods, by restriction enzyme digestion, by PCR amplification, etc. Isolated polynucleotides and polynucleotide fragments of the invention comprise at least about 10, about 15, about 20, about 35, about 50, about 100, about 150 to about 200, about 250 to about 300, or about 350 contiguous nt selected from the polynucleotide sequences as shown in SEQ ID NOS:1–2707. For the most part, fragments will be of at least 15 nt, usually at least 18 nt or 25 nt, and up to at least about 50 contiguous nt in length or more. In a preferred embodiment, the polynucleotide molecules comprise a contiguous sequence of at least 12 nt selected from the group consisting of the polynucleotides shown in SEQ ID NOS:1–2707.

Probes specific to the polynucleotides of the invention can be generated using the polynucleotide sequences disclosed in SEQ ID NOS:1–2707. The probes are preferably at least about a 12, 15, 16, 18, 20, 22, 24, or 25 nt fragment of a corresponding contiguous sequence of SEQ ID NOS:1–2707, and can be less than 2, 1, 0.5, 0.1, or 0.05 kb in length. The probes can be synthesized chemically or can be generated from longer polynucleotides using restriction enzymes. The probes can be labeled, for example, with a radioactive, biotinylated, or fluorescent tag. Preferably, probes are designed based upon an identifying sequence of a polynucleotide of one of SEQ ID NOS:1–2707. More preferably, probes are designed based on a contiguous sequence of one of the subject polynucleotides that remain unmasked following application of a masking program for masking low complexity (e.g., XBLAST) to the sequence., i.e., one would select an unmasked region, as indicated by the polynucleotides outside the poly-n stretches of the masked sequence produced by the masking program.

The polynucleotides of the subject invention are isolated and obtained in substantial purity, generally as other than an intact chromosome. Usually, the polynucleotides, either as DNA or RNA, will be obtained substantially free of other naturally-occurring nucleic acid sequences, generally being at least about 50%, usually at least about 90% pure and are typically “recombinant”, e.g., flanked by one or more nucleotides with which it is not normally associated on a naturally occurring chromosome.

The polynucleotides of the invention can be provided as a linear molecule or within a circular molecule, and can be provided within autonomously replicating molecules (vectors) or within molecules without replication sequences. Expression of the polynucleotides can be regulated by their own or by other regulatory sequences known in the art. The polynucleotides of the invention can be introduced into suitable host cells using a variety of techniques available in the art, such as transferrin polycation-mediated DNA transfer, transfection with naked or encapsulated nucleic acids, liposome-mediated DNA transfer, intracellular transportation of DNA-coated latex beads, protoplast fusion, viral infection, electroporation, gene gun, calcium phosphate-mediated transfection, and the like.

The subject nucleic acid compositions can be used to, for example, produce polypeptides, as probes for the detection of mRNA of the invention in biological samples (e.g., extracts of human cells) to generate additional copies of the polynucleotides, to generate ribozymes or antisense oligonucleotides, and as single stranded DNA probes or as triple-strand forming oligonucleotides. The probes described herein can be used to, for example, determine the presence or absence of the polynucleotide sequences as shown in SEQ ID NOS:1–2707 or variants thereof in a sample. These and other uses are described in more detail below.

Use of Polynucleotides to Obtain Full-Length cDNA, Gene, and Promoter Region

Full-length cDNA molecules comprising the disclosed polynucleotides are obtained as follows. A polynucleotide having a sequence of one of SEQ ID NOS:1–2707, or a portion thereof comprising at least 12, 15, 18, or 20 nt, is used as a hybridization probe to detect hybridizing members of a cDNA library using probe design methods, cloning methods, and clone selection techniques such as those described in U.S. Pat. No. 5,654,173. Libraries of cDNA are made from selected tissues, such as normal or tumor tissue, or from tissues of a mammal treated with, for example, a pharmaceutical agent. Preferably, the tissue is the same as the tissue from which the polynucleotides of the invention were isolated, as both the polynucleotides described herein and the cDNA represent expressed genes. Most preferably, the cDNA library is made from the biological material described herein in the Examples. The choice of cell type for library construction can be made after the identity of the protein encoded by the gene corresponding to the polynucleotide of the invention is known. This will indicate which tissue and cell types are likely to express the related gene, and thus represent a suitable source for the mRNA for generating the cDNA. Where the provided polynucleotides are isolated from cDNA libraries, the libraries are prepared from mRNA of human colon cells, more preferably, human colon cancer cells, even more preferably, from a highly metastatic colon cell, Km 12L4-A.

Techniques for producing and probing nucleic acid sequence libraries are described, for example, in Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd Ed., (1989) Cold Spring Harbor Press, Cold Spring Harbor, N.Y. The cDNA can be prepared by using primers based on sequence from SEQ ID NOS:1–2707. In one embodiment, the cDNA library can be made from only poly-adenylated mRNA. Thus, poly-T primers can be used to prepare cDNA from the mRNA.

Members of the library that are larger than the provided polynucleotides, and preferably that encompass the complete coding sequence of the native message, are obtained. In order to confirm that the entire cDNA has been obtained, RNA protection experiments are performed as follows. Hybridization of a full-length cDNA to an mRNA will protect the RNA from RNase degradation. If the cDNA is not full length, then the portions of the mRNA that are not hybridized will be subject to RNase degradation. This is assayed, as is known in the art, by changes in electrophoretic mobility on polyacrylamide gels, or by detection of released monoribonucleotides. Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd Ed., (1989) Cold Spring Harbor Press, Cold Spring Harbor, N.Y. In order to obtain additional sequences 5′ to the end of a partial cDNA, 5′ RACE (PCR Protocols: A Guide to Methods and Applications, (1990) Academic Press, Inc.) can be performed.

Genomic DNA is isolated using the provided polynucleotides in a manner similar to the isolation of full-length cDNAs. Briefly, the provided polynucleotides, or portions thereof, are used as probes to libraries of genomic DNA. Preferably, the library is obtained from the cell type that was used to generate the polynucleotides of the invention, but this is not essential. Most preferably, the genomic DNA is obtained from the biological material described herein in the Examples. Such libraries can be in vectors suitable for carrying large segments of a genome, such as P1 or YAC, as described in detail in Sambrook et al., 9.4–9.30. In addition, genomic sequences can be isolated from human BAC libraries, which are commercially available from Research Genetics, Inc., Huntsville, Ala., USA, for example. In order to obtain additional 5′ or 3′ sequences, chromosome walking is performed, as described in Sambrook et al., such that adjacent and overlapping fragments of genomic DNA are isolated. These are mapped and pieced together, as is known in the art, using restriction digestion enzymes and DNA ligase.

Using the polynucleotide sequences of the invention, corresponding full-length genes can be isolated using both classical and PCR methods to construct and probe cDNA libraries. Using either method, Northern blots, preferably, are performed on a number of cell types to determine which cell lines express the gene of interest at the highest level. Classical methods of constructing cDNA libraries are taught in Sambrook et al., supra. With these methods, cDNA can be produced from mRNA and inserted into viral or expression vectors. Typically, libraries of mRNA comprising poly(A) tails can be produced with poly(T) primers. Similarly, cDNA libraries can be produced using the instant sequences as primers.

PCR methods are used to amplify the members of a cDNA library that comprise the desired insert. In this case, the desired insert will contain sequence from the full length cDNA that corresponds to the instant polynucleotides. Such PCR methods include gene trapping and RACE methods. Gene trapping entails inserting a member of a cDNA library into a vector. The vector then is denatured to produce single stranded molecules. Next, a substrate-bound probe, such a biotinylated oligo, is used to trap cDNA inserts of interest. Biotinylated probes can be linked to an avidin-bound solid substrate. PCR methods can be used to amplify the trapped cDNA. To trap sequences corresponding to the full length genes, the labeled probe sequence is based on the polynucleotide sequences of the invention. Random primers or primers specific to the library vector can be used to amplify the trapped cDNA. Such gene trapping techniques are described in Gruber et al., WO 95/04745 and Gruber et al., U.S. Pat. No. 5,500,356. Kits are commercially available to perform gene trapping experiments from, for example, Life Technologies, Gaithersburg, Md., USA.

“Rapid amplification of cDNA ends,” or RACE, is a PCR method of amplifying cDNAs from a number of different RNAs. The cDNAs are ligated to an oligonucleotide linker, and amplified by PCR using two primers. One primer is based on sequence from the instant polynucleotides, for which full length sequence is desired, and a second primer comprises sequence that hybridizes to the oligonucleotide linker to amplify the cDNA. A description of this methods is reported in WO 97/19110. In preferred embodiments of RACE, a common primer is designed to anneal to an arbitrary adaptor sequence ligated to cDNA ends (Apte and Siebert, Biotechniques (1993) 15:890–893; Edwards et al., Nuc. Acids Res. (1991) 19:5227–5232). When a single gene-specific RACE primer is paired with the common primer, preferential amplification of sequences between the single gene specific primer and the common primer occurs. Commercial cDNA pools modified for use in RACE are available.

Another PCR-based method generates full-length cDNA library with anchored ends without needing specific knowledge of the cDNA sequence. The method uses lock-docking primers (I–VI), where one primer, poly TV (I–III) locks over the polyA tail of eukaryotic mRNA producing first strand synthesis and a second primer, polyGH (IV–VI) locks onto the polyC tail added by terminal deoxynucleotidyl transferase (TdT)(see, e.g., WO 96/40998).

The promoter region of a gene generally is located 5′ to the initiation site for RNA polymerase II. Hundreds of promoter regions contain the “TATA” box, a sequence such as TATTA or TATAA, which is sensitive to mutations. The promoter region can be obtained by performing 5′ RACE using a primer from the coding region of the gene. Alternatively, the cDNA can be used as a probe for the genomic sequence, and the region 5′ to the coding region is identified by “walking up.” If the gene is highly expressed or differentially expressed, the promoter from the gene can be of use in a regulatory construct for a heterologous gene.

Once the full-length cDNA or gene is obtained, DNA encoding variants can be prepared by site-directed mutagenesis, described in detail in Sambrook et al., 15.3–15.63. The choice of codon or nucleotide to be replaced can be based on disclosure herein on optional changes in amino acids to achieve altered protein structure and/or function.

As an alternative method to obtaining DNA or RNA from a biological material, nucleic acid comprising nucleotides having the sequence of one or more polynucleotides of the invention can be synthesized. Thus, the invention encompasses nucleic acid molecules ranging in length from 15 nt (corresponding to at least 15 contiguous nt of one of SEQ ID NOS:1–2707) up to a maximum length suitable for one or more biological manipulations, including replication and expression, of the nucleic acid molecule. The invention includes but is not limited to (a) nucleic acid having the size of a full gene, and comprising at least one of SEQ ID NOS:1–2707; (b) the nucleic acid of (a) also comprising at least one additional gene, operably linked to permit expression of a fusion protein; (c) an expression vector comprising (a) or (b); (d) a plasmid comprising (a) or (b); and (e) a recombinant viral particle comprising (a) or (b). Once provided with the polynucleotides disclosed herein, construction or preparation of (a)–(e) are well within the skill in the art.

The sequence of a nucleic acid comprising at least 15 contiguous nt of at least any one of SEQ ID NOS:1–2707, preferably the entire sequence of at least any one of SEQ ID NOS:1–2707, is not limited and can be any sequence of A, T, G, and/or C (for DNA) and A, U, G, and/or C (for RNA) or modified bases thereof, including inosine and pseudouridine. The choice of sequence will depend on the desired function and can be dictated by coding regions desired, the intron-like regions desired, and the regulatory regions desired. Where the entire sequence of any one of SEQ ID NOS:1–2707 is within the nucleic acid, the nucleic acid obtained is referred to herein as a polynucleotide comprising the sequence of any one of SEQ ID NOS:1–2707.

Expression of Polypeptide Encoded by Full-Length cDNA or Full-Length Gene

The provided polynucleotides (e.g., a polynucleotide having a sequence of one of SEQ ID NOS:1–2707), the corresponding cDNA, or the full-length gene is used to express a partial or complete gene product. Constructs of polynucleotides having sequences of SEQ ID NOS:1–2707 can also be generated synthetically. Alternatively, single-step assembly of a gene and entire plasmid from large numbers of oligodeoxyribonucleotides is described by, e.g., Stemmer et al., Gene (Amsterdam) (1995) 164(1):49–53. In this method, assembly PCR (the synthesis of long DNA sequences from large numbers of oligodeoxyribonucleotides (oligos)) is described. The method is derived from DNA shuffling (Stemmer, Nature (1994) 370:389–391), and does not rely on DNA ligase, but instead relies on DNA polymerase to build increasingly longer DNA fragments during the assembly process.

Appropriate polynucleotide constructs are purified using standard recombinant DNA techniques as described in, for example, Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd Ed., (1989) Cold Spring Harbor Press, Cold Spring Harbor, N.Y., and under current regulations described in United States Dept. of HHS, National Institute of Health (NIH) Guidelines for Recombinant DNA Research. The gene product encoded by a polynucleotide of the invention is expressed in any expression system, including, for example, bacterial, yeast, insect, amphibian and mammalian systems. Vectors, host cells and methods for obtaining expression in same are well known in the art. Suitable vectors and host cells are described in U.S. Pat. No. 5,654,173.

Polynucleotide molecules comprising a polynucleotide sequence provided herein are generally propagated by placing the molecule in a vector. Viral and non-viral vectors are used, including plasmids. The choice of plasmid will depend on the type of cell in which propagation is desired and the purpose of propagation. Certain vectors are useful for amplifying and making large amounts of the desired DNA sequence. Other vectors are suitable for expression in cells in culture. Still other vectors are suitable for transfer and expression in cells in a whole animal or person. The choice of appropriate vector is well within the skill of the art. Many such vectors are available commercially. Methods for preparation of vectors comprising a desired sequence are well known in the art.

The polynucleotides set forth in SEQ ID NOS:1–2707 or their corresponding full-length polynucleotides are linked to regulatory sequences as appropriate to obtain the desired expression properties. These can include promoters (attached either at the 5′ end of the sense strand or at the 3′ end of the antisense strand), enhancers, terminators, operators, repressors, and inducers. The promoters can be regulated or constitutive. In some situations it may be desirable to use conditionally active promoters, such as tissue-specific or developmental stage-specific promoters. These are linked to the desired nucleotide sequence using the techniques described above for linkage to vectors. Any techniques known in the art can be used.

When any of the above host cells, or other appropriate host cells or organisms, are used to replicate and/or express the polynucleotides or nucleic acids of the invention, the resulting replicated nucleic acid, RNA, expressed protein or polypeptide, is within the scope of the invention as a product of the host cell or organism. The product is recovered by any appropriate means known in the art.

Once the gene corresponding to a selected polynucleotide is identified, its expression can be regulated in the cell to which the gene is native. For example, an endogenous gene of a cell can be regulated by an exogenous regulatory sequence as disclosed in U.S. Pat. No. 5,641,670.

Identification of Functional and Structural Motifs of Novel Genes Screening Against Publicly Available Databases

Translations of the nucleotide sequence of the provided polynucleotides, cDNAs or full genes can be aligned with individual known sequences. Similarity with individual sequences can be used to determine the activity of the polypeptides encoded by the polynucleotides of the invention. Also, sequences exhibiting similarity with more than one individual sequence can exhibit activities that are characteristic of either or both individual sequences.

The full length sequences and fragments of the polynucleotide sequences of the nearest neighbors can be used as probes and primers to identify and isolate the full length sequence corresponding to provided polynucleotides. The nearest neighbors can indicate a tissue or cell type to be used to construct a library for the full-length sequences corresponding to the provided polynucleotides.

Typically, a selected polynucleotide is translated in all six frames to determine the best alignment with the individual sequences. The sequences disclosed herein in the Sequence Listing are in a 5′ to 3′ orientation and translation in three frames can be sufficient (with a few specific exceptions as described in the Examples). These amino acid sequences are referred to, generally, as query sequences, which will be aligned with the individual sequences. Databases with individual sequences are described in “Computer Methods for Macromolecular Sequence Analysis” Methods in Enzymology (1996) 266, Doolittle, Academic Press, Inc., a division of Harcourt Brace & Co., San Diego, Calif., USA. Databases include GenBank, EMBL, and DNA Database of Japan (DDBJ).

Query and individual sequences can be aligned using the methods and computer programs described above, and include BLAST 2.0, available over the world wide web at ncbi.nlm.nih.gov/BLAST. See also Altschul, et al. Nucleic Acids Res. (1997) 25:3389–3402. Another alignment algorithm is Fasta, available in the Genetics Computing Group (GCG) package, Madison, Wis., USA, a wholly owned subsidiary of Oxford Molecular Group, Inc. Other techniques for alignment are described in Doolittle, supra. Preferably, an alignment program that permits gaps in the sequence is utilized to align the sequences. The Smith-Waterman is one type of algorithm that permits gaps in sequence alignments. See Meth. Mol. Biol. (1997) 70: 173–187. Also, the GAP program using the Needleman and Wunsch alignment method can be utilized to align sequences. An alternative search strategy uses MPSRCH software, which runs on a MASPAR computer. MPSRCH uses a Smith-Waterman algorithm to score sequences on a massively parallel computer. This approach improves ability to identify sequences that are distantly related matches, and is especially tolerant of small gaps and nucleotide sequence errors. Amino acid sequences encoded by the provided polynucleotides can be used to search both protein and DNA databases. Incorporated herein by reference are all sequences that have been made public as of the filing date of this application by any of the DNA or protein sequence databases, including the patent databases (e.g., GeneSeq). Also incorporated by reference are those sequences that have been submitted to these databases as of the filing date of the present application but not made public until after the filing date of the present application.

Results of individual and query sequence alignments can be divided into three categories: high similarity, weak similarity, and no similarity. Individual alignment results ranging from high similarity to weak similarity provide a basis for determining polypeptide activity and/or structure. Parameters for categorizing individual results include: percentage of the alignment region length where the strongest alignment is found, percent sequence identity, and p value. The percentage of the alignment region length is calculated by counting the number of residues of the individual sequence found in the region of strongest alignment, e.g., contiguous region of the individual sequence that contains the greatest number of residues that are identical to the residues of the corresponding region of the aligned query sequence. This number is divided by the total residue length of the query sequence to calculate a percentage. For example, a query sequence of 20 amino acid residues might be aligned with a 20 amino acid region of an individual sequence. The individual sequence might be identical to amino acid residues 5, 9–15, and 17–19 of the query sequence. The region of strongest alignment is thus the region stretching from residue 9–19, an 11 amino acid stretch. The percentage of the alignment region length is: 11 (length of the region of strongest alignment) divided by (query sequence length) 20 or 55%.

Percent sequence identity is calculated by counting the number of amino acid matches between the query and individual sequence and dividing total number of matches by the number of residues of the individual sequences found in the region of strongest alignment. Thus, the percent identity in the example above would be 10 matches divided by 11 amino acids, or approximately, 90.9%

P value is the probability that the alignment was produced by chance. For a single alignment, the p value can be calculated according to Karlin et al., Proc. Natl. Acad. Sci. (1990) 87:2264 and Karlin et al., Proc. Natl. Acad. Sci. (1993) 90. The p value of multiple alignments using the same query sequence can be calculated using an heuristic approach described in Altschul et al., Nat. Genet. (1994) 6:119. Alignment programs such as BLAST program can calculate the p value. See also Altschul et al., Nucleic Acids Res. (1997) 25:3389–3402.

Another factor to consider for determining identity or similarity is the location of the similarity or identity. Strong local alignment can indicate similarity even if the length of alignment is short. Sequence identity scattered throughout the length of the query sequence also can indicate a similarity between the query and profile sequences. The boundaries of the region where the sequences align can be determined according to Doolittle, supra; BLAST 2.0 (see, e.g., Altschul, et al. Nucleic Acids Res. (1997) 25:3389–3402) or FAST programs; or by determining the area where sequence identity is highest.

High Similarity. In general, in alignment results considered to be of high similarity, the percent of the alignment region length is typically at least about 55% of total length query sequence; more typically, at least about 58%; even more typically; at least about 60% of the total residue length of the query sequence. Usually, percent length of the alignment region can be as much as about 62%; more usually, as much as about 64%; even more usually, as much as about 66%. Further, for high similarity, the region of alignment, typically, exhibits at least about 75% of sequence identity; more typically, at least about 78%; even more typically; at least about 80% sequence identity. Usually, percent sequence identity can be as much as about 82%; more usually, as much as about 84%; even more usually, as much as about 86%.

The p value is used in conjunction with these methods. If high similarity is found, the query sequence is considered to have high similarity with a profile sequence when the p value is less than or equal to about 10⁻²; more usually; less than or equal to about 10⁻³; even more usually; less than or equal to about 10⁻⁴ More typically, the p value is no more than about 10⁻⁵; more typically; no more than or equal to about 10⁻¹⁰; even more typically; no more than or equal to about 10⁻¹⁵ for the query sequence to be considered high similarity.

Weak Similarity. In general, where alignment results considered to be of weak similarity, there is no minimum percent length of the alignment region nor minimum length of alignment. A better showing of weak similarity is considered when the region of alignment is, typically, at least about 15 amino acid residues in length; more typically, at least about 20; even more typically; at least about 25 amino acid residues in length. Usually, length of the alignment region can be as much as about 30 amino acid residues; more usually, as much as about 40; even more usually, as much as about 60 amino acid residues. Further, for weak similarity, the region of alignment, typically, exhibits at least about 35% of sequence identity; more typically, at least about 40%; even more typically; at least about 45% sequence identity. Usually, percent sequence identity can be as much as about 50%; more usually, as much as about 55%; even more usually, as much as about 60%.

If low similarity is found, the query sequence is considered to have weak similarity with a profile sequence when the p value is usually less than or equal to about 10⁻²; more usually; less than or equal to about 10⁻³; even more usually; less than or equal to about 10⁻⁴. More typically, the p value is no more than about 10⁻⁵; more usually; no more than or equal to about 10⁻¹⁰; even more usually; no more than or equal to about 10⁻¹⁵ for the query sequence to be considered weak similarity.

Similarity Determined by Sequence Identity Alone. Sequence identity alone can be used to determine similarity of a query sequence to an individual sequence and can indicate the activity of the sequence. Such an alignment, preferably, permits gaps to align sequences. Typically, the query sequence is related to the profile sequence if the sequence identity over the entire query sequence is at least about 15%; more typically, at least about 20%; even more typically, at least about 25%; even more typically, at least about 50%. Sequence identity alone as a measure of similarity is most useful when the query sequence is usually, at least 80 residues in length; more usually, 90 residues; even more usually, at least 95 amino acid residues in length. More typically, similarity can be concluded based on sequence identity alone when the query sequence is preferably 100 residues in length; more preferably, 120 residues in length; even more preferably, 150 amino acid residues in length.

Alignments with Profile and Multiple Aligned Sequences. Translations of the provided polynucleotides can be aligned with amino acid profiles that define either protein families or common motifs. Also, translations of the provided polynucleotides can be aligned to multiple sequence alignments (MSA) comprising the polypeptide sequences of members of protein families or motifs. Similarity or identity with profile sequences or MSAs can be used to determine the activity of the gene products (e.g., polypeptides) encoded by the provided polynucleotides or corresponding cDNA or genes. For example, sequences that show an identity or similarity with a chemokine profile or MSA can exhibit chemokine activities.

Profiles can designed manually by (1) creating an MSA, which is an alignment of the amino acid sequence of members that belong to the family and (2) constructing a statistical representation of the alignment. Such methods are described, for example, in Birney et al., Nucl. Acid Res. (1996) 24(14): 2730–2739. MSAs of some protein families and motifs are publicly available. For example, genome.wustl.edu/Pfam includes MSAs of 547 different families and motifs. These MSAs are described also in Sonnhammer et al., Proteins (1997) 28: 405–420. Other sources over the world wide web include the site at embl-heidelberg.de/argos/ali/ali. A brief description of these MSAs is reported in Pascarella et al., Prot. Eng. (1996) 9(3):249–251. Techniques for building profiles from MSAs are described in Sonnhammer et al., supra; Birney et al., supra; and “Computer Methods for Macromolecular Sequence Analysis,” Methods in Enzymology (1996) 266, Doolittle, Academic Press, Inc., San Diego, Calif., USA.

Similarity between a query sequence and a protein family or motif can be determined by (a) comparing the query sequence against the profile and/or (b) aligning the query sequence with the members of the family or motif. Typically, a program such as Searchwise is used to compare the query sequence to the statistical representation of the multiple alignment, also known as a profile (see Birney et al., supra). Other techniques to compare the sequence and profile are described in Sonnhammer et al., supra and Doolittle, supra.

Next, methods described by Feng et al., J. Mol. Evol. (1987) 25:351 and Higgins et al., CABIOS (1989) 5:151 can be used align the query sequence with the members of a family or motif, also known as a MSA. Sequence alignments can be generated using any of a variety of software tools. Examples include PileUp, which creates a multiple sequence alignment, and is described in Feng et al, J. Mol. Evol. (1987) 25:351. Another method, GAP, uses the alignment method of Needleman et al., J. Mol. Biol. (1970) 48:443. GAP is best suited for global alignment of sequences. A third method, BestFit, functions by inserting gaps to maximize the number of matches using the local homology algorithm of Smith et al., Adv. Appl. Math. (1981) 2:482. In general, the following factors are used to determine if a similarity between a query sequence and a profile or MSA exists: (1) number of conserved residues found in the query sequence, (2) percentage of conserved residues found in the query sequence, (3) number of frameshifts, and (4) spacing between conserved residues.

Some alignment programs that both translate and align sequences can make any number of frameshifts when translating the nucleotide sequence to produce the best alignment. The fewer frameshifts needed to produce an alignment, the stronger the similarity or identity between the query and profile or MSAs. For example, a weak similarity resulting from no frameshifts can be a better indication of activity or structure of a query sequence, than a strong similarity resulting from two frameshifts. Preferably, three or fewer frameshifts are found in an alignment; more preferably two or fewer frameshifts; even more preferably, one or fewer frameshifts; even more preferably, no frameshifts are found in an alignment of query and profile or MSAs.

Conserved residues are those amino acids found at a particular position in all or some of the family or motif members. Alternatively, a position is considered conserved if only a certain class of amino acids is found in a particular position in all or some of the family members. For example, the N-terminal position can contain a positively charged amino acid, such as lysine, arginine, or histidine.

Typically, a residue of a polypeptide is conserved when a class of amino acids or a single amino acid is found at a particular position in at least about 40% of all class members; more typically, at least about 50%; even more typically, at least about 60% of the members. Usually, a residue is conserved when a class or single amino acid is found in at least about 70% of the members of a family or motif; more usually, at least about 80%; even more usually, at least about 90%; even more usually, at least about 95%.

A residue is considered conserved when three unrelated amino acids are found at a particular position in the some or all of the members; more usually, two unrelated amino acids. These residues are conserved when the unrelated amino acids are found at particular positions in at least about 40% of all class member; more typically, at least about 50%; even more typically, at least about 60% of the members. Usually, a residue is conserved when a class or single amino acid is found in at least about 70% of the members of a family or motif; more usually, at least about 80%; even more usually, at least about 90%; even more usually, at least about 95%.

A query sequence has similarity to a profile or MSA when the query sequence comprises at least about 25% of the conserved residues of the profile or MSA; more usually, at least about 30%; even more usually; at least about 40%. Typically, the query sequence has a stronger similarity to a profile sequence or MSA when the query sequence comprises at least about 45% of the conserved residues of the profile or MSA; more typically, at least about 50%; even more typically; at least about 55%.

Identification of Secreted & Membrane-Bound Polypeptides

Both secreted and membrane-bound polypeptides of the present invention are of particular interest. For example, levels of secreted polypeptides can be assayed in body fluids that are convenient, such as blood, plasma, serum, and other body fluids such as urine, prostatic fluid and semen. Membrane-bound polypeptides are useful for constructing vaccine antigens or inducing an immune response. Such antigens would comprise all or part of the extracellular region of the membrane-bound polypeptides. Because both secreted and membrane-bound polypeptides comprise a fragment of contiguous hydrophobic amino acids, hydrophobicity predicting algorithms can be used to identify such polypeptides.

A signal sequence is usually encoded by both secreted and membrane-bound polypeptide genes to direct a polypeptide to the surface of the cell. The signal sequence usually comprises a stretch of hydrophobic residues. Such signal sequences can fold into helical structures. Membrane-bound polypeptides typically comprise at least one transmembrane region that possesses a stretch of hydrophobic amino acids that can transverse the membrane. Some transmembrane regions also exhibit a helical structure. Hydrophobic fragments within a polypeptide can be identified by using computer algorithms. Such algorithms include Hopp & Woods, Proc. Natl. Acad. Sci. USA (1981) 78:3824–3828; Kyte & Doolittle, J. Mol. Biol. (1982) 157:105–132; and RAOAR algorithm, Degli Esposti et al., Eur. J. Biochem. (1990) 190: 207–219.

Another method of identifying secreted and membrane-bound polypeptides is to translate the polynucleotides of the invention in all six frames and determine if at least 8 contiguous hydrophobic amino acids are present. Those translated polypeptides with at least 8; more typically, 10; even more typically, 12 contiguous hydrophobic amino acids are considered to be either a putative secreted or membrane bound polypeptide. Hydrophobic amino acids include alanine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, threonine, tryptophan, tyrosine, and valine

Identification of the Function of an Expression Product of a Full-Length Gene

Ribozymes, antisense constructs, and dominant negative mutants can be used to determine function of the expression product of a gene corresponding to a polynucleotide provided herein. These methods and compositions are particularly useful where the provided novel polynucleotide exhibits no significant or substantial homology to a sequence encoding a gene of known function. Antisense molecules and ribozymes can be constructed from synthetic polynucleotides. Typically, the phosphoramidite method of oligonucleotide synthesis is used. See Beaucage et al., Tet. Lett. (1981) 22:1859 and U.S. Pat. No. 4,668,777. Automated devices for synthesis are available to create oligonucleotides using this chemistry. Examples of such devices include Biosearch 8600, Models 392 and 394 by Applied Biosystems, a division of Perkin-Elmer Corp., Foster City, Calif., USA; and Expedite by Perceptive Biosystems, Framingham, Mass., USA. Synthetic RNA, phosphate analog oligonucleotides, and chemically derivatized oligonucleotides can also be produced, and can be covalently attached to other molecules. RNA oligonucleotides can be synthesized, for example, using RNA phosphoramidites. This method can be performed on an automated synthesizer, such as Applied Biosystems, Models 392 and 394, Foster City, Calif., USA.

Phosphorothioate oligonucleotides can also be synthesized for antisense construction. A sulfurizing reagent, such as tetraethylthiruam disulfide (TETD) in acetonitrile can be used to convert the internucleotide cyanoethyl phosphite to the phosphorothioate triester within 15 minutes at room temperature. TETD replaces the iodine reagent, while all other reagents used for standard phosphoramidite chemistry remain the same. Such a synthesis method can be automated using Models 392 and 394 by Applied Biosystems, for example.

Oligonucleotides of up to 200 nt can be synthesized, more typically, 100 nt, more typically 50 nt; even more typically 30 to 40 nt. These synthetic fragments can be annealed and ligated together to construct larger fragments. See, for example, Sambrook et al., supra. Trans-cleaving catalytic RNAs (ribozymes) are RNA molecules possessing endoribonuclease activity. Ribozymes are specifically designed for a particular target, and the target message must contain a specific nucleotide sequence. They are engineered to cleave any RNA species site-specifically in the background of cellular RNA. The cleavage event renders the mRNA unstable and prevents protein expression. Importantly, ribozymes can be used to inhibit expression of a gene of unknown function for the purpose of determining its function in an in vitro or in vivo context, by detecting the phenotypic effect. One commonly used ribozyme motif is the hammerhead, for which the substrate sequence requirements are minimal. Design of the hammerhead ribozyme, as well as therapeutic uses of ribozymes, are disclosed in Usman et al., Current Opin. Struct. Biol. (1996) 6:527. Methods for production of ribozymes, including hairpin structure ribozyme fragments, methods of increasing ribozyme specificity, and the like are known in the art.

The hybridizing region of the ribozyme can be modified or can be prepared as a branched structure as described in Horn and Urdea, Nucleic Acids Res. (1989) 17:6959. The basic structure of the ribozymes can also be chemically altered in ways familiar to those skilled in the art, and chemically synthesized ribozymes can be administered as synthetic oligonucleotide derivatives modified by monomeric units. In a therapeutic context, liposome mediated delivery of ribozymes improves cellular uptake, as described in Birikh et al., Eur. J. Biochem. (1997) 245:1.

Antisense nucleic acids are designed to specifically bind to RNA, resulting in the formation of RNA-DNA or RNA-RNA hybrids, with an arrest of DNA replication, reverse transcription or messenger RNA translation. Antisense polynucleotides based on a selected polynucleotide sequence can interfere with expression of the corresponding gene. Antisense polynucleotides are typically generated within the cell by expression from antisense constructs that contain the antisense strand as the transcribed strand. Antisense polynucleotides based on the disclosed polynucleotides will bind and/or interfere with the translation of mRNA comprising a sequence complementary to the antisense polynucleotide. The expression products of control cells and cells treated with the antisense construct are compared to detect the protein product of the gene corresponding to the polynucleotide upon which the antisense construct is based. The protein is isolated and identified using routine biochemical methods.

Given the extensive background literature and clinical experience in antisense therapy, one skilled in the art can use selected polynucleotides of the invention as additional potential therapeutics. The choice of polynucleotide can be narrowed by first testing them for binding to “hot spot” regions of the genome of cancerous cells. If a polynucleotide is identified as binding to a “hot spot”, testing the polynucleotide as an antisense compound in the corresponding cancer cells is warranted.

As an alternative method for identifying function of the gene corresponding to a polynucleotide disclosed herein, dominant negative mutations are readily generated for corresponding proteins that are active as homomultimers. A mutant polypeptide will interact with wild-type polypeptides (made from the other allele) and form a non-functional multimer. Thus, a mutation is in a substrate-binding domain, a catalytic domain, or a cellular localization domain. Preferably, the mutant polypeptide will be overproduced. Point mutations are made that have such an effect. In addition, fusion of different polypeptides of various lengths to the terminus of a protein can yield dominant negative mutants. General strategies are available for making dominant negative mutants (see, e.g., Herskowitz, Nature (1987) 329:219). Such techniques can be used to create loss of function mutations, which are useful for determining protein function.

Polypeptides and Variants Thereof

The polypeptides of the invention include those encoded by the disclosed polynucleotides, as well as nucleic acids that, by virtue of the degeneracy of the genetic code, are not identical in sequence to the disclosed polynucleotides. Thus, the invention includes within its scope a polypeptide encoded by a polynucleotide having the sequence of any one of SEQ ID NOS:1–2707 or a variant thereof.

In general, the term “polypeptide” as used herein refers to both the full length polypeptide encoded by the recited polynucleotide, the polypeptide encoded by the gene represented by the recited polynucleotide, as well as portions or fragments thereof. “Polypeptides” also includes variants of the naturally occurring proteins, where such variants are homologous or substantially similar to the naturally occurring protein, and can be of an origin of the same or different species as the naturally occurring protein (e.g., human, murine, or some other species that naturally expresses the recited polypeptide, usually a mammalian species). In general, variant polypeptides have a sequence that has at least about 80%, usually at least about 90%, and more usually at least about 98% sequence identity with a differentially expressed polypeptide of the invention, as measured by BLAST 2.0 using the parameters described above. The variant polypeptides can be naturally or non-naturally glycosylated, i.e., the polypeptide has a glycosylation pattern that differs from the glycosylation pattern found in the corresponding naturally occurring protein.

The invention also encompasses homologs of the disclosed polypeptides (or fragments thereof) where the homologs are isolated from other species, i.e. other animal or plant species, where such homologs, usually mammalian species, e.g. rodents, such as mice, rats; domestic animals, e.g., horse, cow, dog, cat; and humans. By “homolog” is meant a polypeptide having at least about 35%, usually at least about 40% and more usually at least about 60% amino acid sequence identity to a particular differentially expressed protein as identified above, where sequence identity is determined using the BLAST 2.0 algorithm, with the parameters described supra.

In general, the polypeptides of the subject invention are provided in a non-naturally occurring environment, e.g. are separated from their naturally occurring environment. In certain embodiments, the subject protein is present in a composition that is enriched for the protein as compared to a control. As such, purified polypeptide is provided, where by purified is meant that the protein is present in a composition that is substantially free of non-differentially expressed polypeptides, where by substantially free is meant that less than 90%, usually less than 60% and more usually less than 50% of the composition is made up of non-differentially expressed polypeptides.

Also within the scope of the invention are variants; variants of polypeptides include mutants, fragments, and fusions. Mutants can include amino acid substitutions, additions or deletions. The amino acid substitutions can be conservative amino acid substitutions or substitutions to eliminate non-essential amino acids, such as to alter a glycosylation site, a phosphorylation site or an acetylation site, or to minimize misfolding by substitution or deletion of one or more cysteine residues that are not necessary for function. Conservative amino acid substitutions are those that preserve the general charge, hydrophobicity/hydrophilicity, and/or steric bulk of the amino acid substituted. Variants can be designed so as to retain or have enhanced biological activity of a particular region of the protein (e.g., a functional domain and/or, where the polypeptide is a member of a protein family, a region associated with a consensus sequence). Selection of amino acid alterations for production of variants can be based upon the accessibility (interior vs. exterior) of the amino acid (see, e.g., Go et al, Int. J. Peptide Protein Res. (1980) 15:211), the thermostability of the variant polypeptide (see, e.g., Querol et al., Prot. Eng. (1996) 9:265), desired glycosylation sites (see, e.g., Olsen and Thomsen, J. Gen. Microbiol. (1991) 137:579), desired disulfide bridges (see, e.g., Clarke et al., Biochemistry (1993) 32:4322; and Wakarchuk et al., Protein Eng. (1994) 7:1379), desired metal binding sites (see, e.g., Toma et al., Biochemistry (1991) 30:97, and Haezerbrouck et al., Protein Eng. (1993) 6:643), and desired substitutions with in proline loops (see, e.g., Masul et al., Appl. Env. Microbiol. (1994) 60:3579). Cysteine-depleted muteins can be produced as disclosed in U.S. Pat. No. 4,959,314.

Variants also include fragments of the polypeptides disclosed herein, particularly biologically active fragments and/or fragments corresponding to functional domains. Fragments of interest will typically be at least about 10 aa to at least about 15 aa in length, usually at least about 50 aa in length, and can be as long as 300 aa in length or longer, but will usually not exceed about 1000 aa in length, where the fragment will have a stretch of amino acids that is identical to a polypeptide encoded by a polynucleotide having a sequence of any SEQ ID NOS:1–2707, or a homolog thereof. The protein variants described herein are encoded by polynucleotides that are within the scope of the invention. The genetic code can be used to select the appropriate codons to construct the corresponding variants.

Computer-Related Embodiments

In general, a library of polynucleotides is a collection of sequence information, which information is provided in either biochemical form (e.g., as a collection of polynucleotide molecules), or in electronic form (e.g., as a collection of polynucleotide sequences stored in a computer-readable form, as in a computer system and/or as part of a computer program). The sequence information of the polynucleotides can be used in a variety of ways, e.g., as a resource for gene discovery, as a representation of sequences expressed in a selected cell type (e.g., cell type markers), and/or as markers of a given disease or disease state. In general, a disease marker is a representation of a gene product that is present in all cells affected by disease either at an increased or decreased level relative to a normal cell (e.g., a cell of the same or similar type that is not substantially affected by disease). For example, a polynucleotide sequence in a library can be a polynucleotide that represents an mRNA, polypeptide, or other gene product encoded by the polynucleotide, that is either overexpressed or underexpressed in a breast ductal cell affected by cancer relative to a normal (i.e., substantially disease-free) breast cell.

The nucleotide sequence information of the library can be embodied in any suitable form, e.g., electronic or biochemical forms. For example, a library of sequence information embodied in electronic form comprises an accessible computer data file (or, in biochemical form, a collection of nucleic acid molecules) that contains the representative nucleotide sequences of genes that are differentially expressed (e.g., overexpressed or underexpressed) as between, for example, i) a cancerous cell and a normal cell; ii) a cancerous cell and a dysplastic cell; iii) a cancerous cell and a cell affected by a disease or condition other than cancer; iv) a metastatic cancerous cell and a normal cell and/or non-metastatic cancerous cell; v) a malignant cancerous cell and a non-malignant cancerous cell (or a normal cell) and/or vi) a dysplastic cell relative to a normal cell. Other combinations and comparisons of cells affected by various diseases or stages of disease will be readily apparent to the ordinarily skilled artisan. Biochemical embodiments of the library include a collection of nucleic acids that have the sequences of the genes in the library, where the nucleic acids can correspond to the entire gene in the library or to a fragment thereof, as described in greater detail below.

The polynucleotide libraries of the subject invention generally comprise sequence information of a plurality of polynucleotide sequences, where at least one of the polynucleotides has a sequence of any of SEQ ID NOS:1–2707. By plurality is meant at least 2, usually at least 3 and can include up to all of SEQ ID NOS:1–2707. The length and number of polynucleotides in the library will vary with the nature of the library, e.g., if the library is an oligonucleotide array, a cDNA array, a computer database of the sequence information, etc.

Where the library is an electronic library, the nucleic acid sequence information can be present in a variety of media. “Media” refers to a manufacture, other than an isolated nucleic acid molecule, that contains the sequence information of the present invention. Such a manufacture provides the genome sequence or a subset thereof in a form that can be examined by means not directly applicable to the sequence as it exists in a nucleic acid. For example, the nucleotide sequence of the present invention, e.g. the nucleic acid sequences of any of the polynucleotides of SEQ ID NOS:1–2707, can be recorded on computer readable media, e.g. any medium that can be read and accessed directly by a computer. Such media include, but are not limited to: magnetic storage media, such as a floppy disc, a hard disc storage medium, and a magnetic tape; optical storage media such as CD-ROM; electrical storage media such as RAM and ROM; and hybrids of these categories such as magnetic/optical storage media. One of skill in the art can readily appreciate how any of the presently known computer readable mediums can be used to create a manufacture comprising a recording of the present sequence information. “Recorded” refers to a process for storing information on computer readable medium, using any such methods as known in the art. Any convenient data storage structure can be chosen, based on the means used to access the stored information. A variety of data processor programs and formats can be used for storage, e.g. word processing text file, database format, etc. In addition to the sequence information, electronic versions of the libraries of the invention can be provided in conjunction or connection with other computer-readable information and/or other types of computer-readable files (e.g., searchable files, executable files, etc, including, but not limited to, for example, search program software, etc.).

By providing the nucleotide sequence in computer readable form, the information can be accessed for a variety of purposes. Computer software to access sequence information is publicly available. For example, the gapped BLAST (Altschul et al. Nucleic Acids Res. (1997) 25:3389–3402) and BLAZE (Brutlag et al. Comp. Chem. (1993) 17:203) search algorithms on a Sybase system can be used to identify open reading frames (ORFs) within the genome that contain homology to ORFs from other organisms.

As used herein, “a computer-based system” refers to the hardware means, software means, and data storage means used to analyze the nucleotide sequence information of the present invention. The minimum hardware of the computer-based systems of the present invention comprises a central processing unit (CPU), input means, output means, and data storage means. A skilled artisan can readily appreciate that any one of the currently available computer-based system are suitable for use in the present invention. The data storage means can comprise any manufacture comprising a recording of the present sequence information as described above, or a memory access means that can access such a manufacture.

“Search means” refers to one or more programs implemented on the computer-based system, to compare a target sequence or target structural motif, or expression levels of a polynucleotide in a sample, with the stored sequence information. Search means can be used to identify fragments or regions of the genome that match a particular target sequence or target motif. A variety of known algorithms are publicly known and commercially available, e.g. MacPattern (EMBL), BLASTN and BLASTX (NCBI). A “target sequence” can be any polynucleotide or amino acid sequence of six or more contiguous nucleotides or two or more amino acids, preferably from about 10 to 100 amino acids or from about 30 to 300 nt A variety of comparing means can be used to accomplish comparison of sequence information from a sample (e.g., to analyze target sequences, target motifs, or relative expression levels) with the data storage means. A skilled artisan can readily recognize that any one of the publicly available homology search programs can be used as the search means for the computer based systems of the present invention to accomplish comparison of target sequences and motifs. Computer programs to analyze expression levels in a sample and in controls are also known in the art.

A “target structural motif,” or “target motif,” refers to any rationally selected sequence or combination of sequences in which the sequence(s) are chosen based on a three-dimensional configuration that is formed upon the folding of the target motif, or on consensus sequences of regulatory or active sites. There are a variety of target motifs known in the art. Protein target motifs include, but are not limited to, enzyme active sites and signal sequences. Nucleic acid target motifs include, but are not limited to, hairpin structures, promoter sequences and other expression elements such as binding sites for transcription factors.

A variety of structural formats for the input and output means can be used to input and output the information in the computer-based systems of the present invention. One format for an output means ranks the relative expression levels of different polynucleotides. Such presentation provides a skilled artisan with a ranking of relative expression levels to determine a gene expression profile.

As discussed above, the “library” of the invention also encompasses biochemical libraries of the polynucleotides of SEQ ID NOS:1–2707, e.g., collections of nucleic acids representing the provided polynucleotides. The biochemical libraries can take a variety of forms, e.g., a solution of cDNAs, a pattern of probe nucleic acids stably associated with a surface of a solid support (i.e., an array) and the like. Of particular interest are nucleic acid arrays in which one or more of SEQ ID NOS:1–2707 is represented on the array. By array is meant a an article of manufacture that has at least a substrate with at least two distinct nucleic acid targets on one of its surfaces, where the number of distinct nucleic acids can be considerably higher, typically being at least 10 nt, usually at least 20 nt and often at least 25 nt. A variety of different array formats have been developed and are known to those of skill in the art. The arrays of the subject invention find use in a variety of applications, including gene expression analysis, drug screening, mutation analysis and the like, as disclosed in the above-listed exemplary patent documents.

In addition to the above nucleic acid libraries, analogous libraries of polypeptides are also provided, where the where the polypeptides of the library will represent at least a portion of the polypeptides encoded by SEQ ID NOS:1–2707.

Utilities

Use of Polynucleotide Probes in Mapping, and in Tissue Profiling

Polynucleotide probes, generally comprising at least 12 contiguous nt of a polynucleotide as shown in the Sequence Listing, are used for a variety of purposes, such as chromosome mapping of the polynucleotide and detection of transcription levels. Additional disclosure about preferred regions of the disclosed polynucleotide sequences is found in the Examples. A probe that hybridizes specifically to a polynucleotide disclosed herein should provide a detection signal at least 5-, 10-, or 20-fold higher than the background hybridization provided with other unrelated sequences.

Detection of Expression Levels. Nucleotide probes are used to detect expression of a gene corresponding to the provided polynucleotide. In Northern blots, mRNA is separated electrophoretically and contacted with a probe. A probe is detected as hybridizing to an mRNA species of a particular size. The amount of hybridization is quantitated to determine relative amounts of expression, for example under a particular condition. Probes are used for in situ hybridization to cells to detect expression. Probes can also be used in vivo for diagnostic detection of hybridizing sequences. Probes are typically labeled with a radioactive isotope. Other types of detectable labels can be used such as chromophores, fluors, and enzymes. Other examples of nucleotide hybridization assays are described in WO92/02526 and U.S. Pat. No. 5,124,246.

Alternatively, the Polymerase Chain Reaction (PCR) is another means for detecting small amounts of target nucleic acids (see, e.g., Mullis et al., Meth. Enzymol. (1987) 155:335; U.S. Pat. No. 4,683,195; and U.S. Pat. No. 4,683,202). Two primer polynucleotides nucleotides that hybridize with the target nucleic acids are used to prime the reaction. The primers can be composed of sequence within or 3′ and 5′ to the polynucleotides of the Sequence Listing. Alternatively, if the primers are 3′ and 5′ to these polynucleotides, they need not hybridize to them or the complements. After amplification of the target with a thermostable polymerase, the amplified target nucleic acids can be detected by methods known in the art, e.g., Southern blot. mRNA or cDNA can also be detected by traditional blotting techniques (e.g., Southern blot, Northern blot, etc.) described in Sambrook et al., “Molecular Cloning: A Laboratory Manual” (New York, Cold Spring Harbor Laboratory, 1989) (e.g., without PCR amplification). In general, mRNA or cDNA generated from mRNA using a polymerase enzyme can be purified and separated using gel electrophoresis, and transferred to a solid support, such as nitrocellulose. The solid support is exposed to a labeled probe, washed to remove any unhybridized probe, and duplexes containing the labeled probe are detected.

Mapping. Polynucleotides of the present invention can be used to identify a chromosome on which the corresponding gene resides. Such mapping can be useful in identifying the function of the polynucleotide-related gene by its proximity to other genes with known function. Function can also be assigned to the polynucleotide-related gene when particular syndromes or diseases map to the same chromosome. For example, use of polynucleotide probes in identification and quantification of nucleic acid sequence aberrations is described in U.S. Pat. No. 5,783,387. An exemplary mapping method is fluorescence in situ hybridization (FISH), which facilitates comparative genomic hybridization to allow total genome assessment of changes in relative copy number of DNA sequences (see, e.g., Valdes et al, Methods in Molecular Biology (1997) 68:1). Polynucleotides can also be mapped to particular chromosomes using, for example, radiation hybrids or chromosome-specific hybrid panels. See Leach et al. Advances in Genetics, (1995) 33:63–99; Walter et al., Nature Genetics (1994) 7:22; Walter and Goodfellow, Trends in Genetics (1992) 9:352. Panels for radiation hybrid mapping are available from Research Genetics, Inc., Huntsville, Ala., USA. Databases for markers using various panels are available via the world wide web at shgc-www.stanford.edu; and www-genome.wi.mit.edu/cgi-bin/contig/rhmapper.pl. The statistical program RHMAP can be used to construct a map based on the data from radiation hybridization with a measure of the relative likelihood of one order versus another. RHMAP is available via the world wide web at http://www.sph.umich.edu/group/statgen/software. In addition, commercial programs are available for identifying regions of chromosomes commonly associated with disease, such as cancer.

Tissue Typing or Profiling. Expression of specific mRNA corresponding to the provided polynucleotides can vary in different cell types and can be tissue-specific. This variation of mRNA levels in different cell types can be exploited with nucleic acid probe assays to determine tissue types. For example, PCR, branched DNA probe assays, or blotting techniques utilizing nucleic acid probes substantially identical or complementary to polynucleotides listed in the Sequence Listing can determine the presence or absence of the corresponding cDNA or mRNA.

Tissue typing can be used to identify the developmental organ or tissue source of a metastatic lesion by identifying the expression of a particular marker of that organ or tissue. If a polynucleotide is expressed only in a specific tissue type, and a metastatic lesion is found to express that polynucleotide, then the developmental source of the lesion has been identified. Expression of a particular polynucleotide can be assayed by detection of either the corresponding mRNA or the protein product. As would be readily apparent to any forensic scientist, the sequences disclosed herein are useful in differentiating human tissue from non-human tissue. In particular, these sequences are useful to differentiate human tissue from bird, reptile, and amphibian tissue, for example.

Use of Polymorphisms. A polynucleotide of the invention can be used in forensics, genetic analysis, mapping, and diagnostic applications where the corresponding region of a gene is polymorphic in the human population. Any means for detecting a polymorphism in a gene can be used, including, but not limited to electrophoresis of protein polymorphic variants, differential sensitivity to restriction enzyme cleavage, and hybridization to allele-specific probes.

Antibody Production

Expression products of a polynucleotide of the invention, as well as the corresponding mRNA, cDNA, or complete gene, can be prepared and used for raising antibodies for experimental, diagnostic, and therapeutic purposes. For polynucleotides to which a corresponding gene has not been assigned, this provides an additional method of identifying the corresponding gene. The polynucleotide or related cDNA is expressed as described above, and antibodies are prepared. These antibodies are specific to an epitope on the polypeptide encoded by the polynucleotide, and can precipitate or bind to the corresponding native protein in a cell or tissue preparation or in a cell-free extract of an in vitro expression system.

Methods for production of antibodies that specifically bind a selected antigen are well known in the art. Immunogens for raising antibodies can be prepared by mixing a polypeptide encoded by a polynucleotide of the invention with an adjuvant, and/or by making fusion proteins with larger immunogenic proteins. Polypeptides can also be covalently linked to other larger immunogenic proteins, such as keyhole limpet hemocyanin. Immunogens are typically administered intradermally, subcutaneously, or intramuscularly to experimental animals such as rabbits, sheep, and mice, to generate antibodies. Monoclonal antibodies can be Monoclonal antibodies can be generated by isolating spleen cells and fusing myeloma cells to form hybridomas. Alternatively, the selected polynucleotide is administered directly, such as by intramuscular injection, and expressed in vivo. The expressed protein generates a variety of protein-specific immune responses, including production of antibodies, comparable to administration of the protein.

Preparations of polyclonal and monoclonal antibodies specific for polypeptides encoded by a selected polynucleotide are made using standard methods known in the art. The antibodies specifically bind to epitopes present in the polypeptides encoded by polynucleotides disclosed in the Sequence Listing. Typically, at least 6, 8, 10, or 12 contiguous amino acids are required to form an epitope. Epitopes that involve non-contiguous amino acids may require a longer polypeptide, e.g., at least 15, 25, or 50 amino acids. Antibodies that specifically bind to human polypeptides encoded by the provided polypeptides should provide a detection signal at least 5-, 10-, or 20-fold higher than a detection signal provided with other proteins when used in Western blots or other immunochemical assays. Preferably, antibodies that specifically polypeptides of the invention do not bind to other proteins in immunochemical assays at detectable levels and can immunoprecipitate the specific polypeptide from solution.

The invention also contemplates naturally occurring antibodies specific for a polypeptide of the invention. For example, serum antibodies to a polypeptide of the invention in a human population can be purified by methods well known in the art, e.g., by passing antiserum over a column to which the corresponding selected polypeptide or fusion protein is bound. The bound antibodies can then be eluted from the column, for example using a buffer with a high salt concentration.

In addition to the antibodies discussed above, the invention also contemplates genetically engineered antibodies, antibody derivatives (e.g., single chain antibodies, antibody fragments (e.g., Fab, etc.)), according to methods well known in the art.

Polynucleotides or Arrays for Diagnostics

Polynucleotide arrays provide a high throughput technique that can assay a large number of polynucleotide sequences in a sample. This technology can be used as a diagnostic and as a tool to test for differential expression, e.g., to determine function of an encoded protein. Arrays can be created by spotting polynucleotide probes onto a substrate (e.g., glass, nitrocelllose, etc.) in a two-dimensional matrix or array having bound probes. The probes can be bound to the substrate by either covalent bonds or by non-specific interactions, such as hydrophobic interactions. Samples of polynucleotides can be detectably labeled (e.g., using radioactive or fluorescent labels) and then hybridized to the probes. Double stranded polynucleotides, comprising the labeled sample polynucleotides bound to probe polynucleotides, can be detected once the unbound portion of the sample is washed away. Techniques for constructing arrays and methods of using these arrays are described in EP 799 897; WO 97/29212; WO 97/27317; EP 785 280; WO 97/02357; U.S. Pat. No. 5,593,839; U.S. Pat. No. 5,578,832; EP 728 520; U.S. Pat. No. 5,599,695; EP 721 016; U.S. Pat. No. 5,556,752; WO 95/22058; and U.S. Pat. No. 5,631,734. Arrays can be used to, for example, examine differential expression of genes and can be used to determine gene function. For example, arrays can be used to detect differential expression of a polynucleotide between a test cell and control cell (e.g., cancer cells and normal cells). For example, high expression of a particular message in a cancer cell, which is not observed in a corresponding normal cell, can indicate a cancer specific gene product. Exemplary uses of arrays are further described in, for example, Pappalarado et al., Sem. Radiation Oncol. (1998) 8:217; and Ramsay Nature Biotechnol. (1998) 16:40.

Differential Expression in Diagnosis

The polynucleotides of the invention can also be used to detect differences in expression levels between two cells, e.g., as a method to identify abnormal or diseased tissue in a human. For polynucleotides corresponding to profiles of protein families, the choice of tissue can be selected according to the putative biological function. In general, the expression of a gene corresponding to a specific polynucleotide is compared between a first tissue that is suspected of being diseased and a second, normal tissue of the human. The tissue suspected of being abnormal or diseased can be derived from a different tissue type of the human, but preferably it is derived from the same tissue type; for example an intestinal polyp or other abnormal growth should be compared with normal intestinal tissue. The normal tissue can be the same tissue as that of the test sample, or any normal tissue of the patient, especially those that express the polynucleotide-related gene of interest (e.g., brain, thymus, testis, heart, prostate, placenta, spleen, small intestine, skeletal muscle, pancreas, and the mucosal lining of the colon). A difference between the polynucleotide-related gene, mRNA, or protein in the two tissues which are compared, for example in molecular weight, amino acid or nucleotide sequence, or relative abundance, indicates a change in the gene, or a gene which regulates it, in the tissue of the human that was suspected of being diseased. Examples of detection of differential expression and its use in diagnosis of cancer are described in U.S. Pat. Nos. 5,688,641 and 5,677,125.

A genetic predisposition to disease in a human can also be detected by comparing expression levels of an mRNA or protein corresponding to a polynucleotide of the invention in a fetal tissue with levels associated in normal fetal tissue. Fetal tissues that are used for this purpose include, but are not limited to, amniotic fluid, chorionic villi, blood, and the blastomere of an in vitro-fertilized embryo. The comparable normal polynucleotide-related gene is obtained from any tissue. The mRNA or protein is obtained from a normal tissue of a human in which the polynucleotide-related gene is expressed. Differences such as alterations in the nucleotide sequence or size of the same product of the fetal polynucleotide-related gene or mRNA, or alterations in the molecular weight, amino acid sequence, or relative abundance of fetal protein, can indicate a germline mutation in the polynucleotide-related gene of the fetus, which indicates a genetic predisposition to disease. In general, diagnostic, prognostic, and other methods of the invention based on differential expression involve detection of a level or amount of a gene product, particularly a differentially expressed gene product, in a test sample obtained from a patient suspected of having or being susceptible to a disease (e.g., breast cancer, lung cancer, colon cancer and/or metastatic forms thereof), and comparing the detected levels to those levels found in normal cells (e.g., cells substantially unaffected by cancer) and/or other control cells (e.g., to differentiate a cancerous cell from a cell affected by dysplasia). Furthermore, the severity of the disease can be assessed by comparing the detected levels of a differentially expressed gene product with those levels detected in samples representing the levels of differentially gene product associated with varying degrees of severity of disease. It should be noted that use of the term “diagnostic” herein is not necessarily meant to exclude “prognostic” or “prognosis,” but rather is used as a matter of convenience.

The term “differentially expressed gene” is generally intended to encompass a polynucleotide that can, for example, include an open reading frame encoding a gene product (e.g., a polypeptide), and/or introns of such genes and adjacent 5′ and 3′ non-coding nucleotide sequences involved in the regulation of expression, up to about 20 kb beyond the coding region, but possibly further in either direction. The gene can be introduced into an appropriate vector for extrachromosomal maintenance or for integration into a host genome. In general, a difference in expression level associated with a decrease in expression level of at least about 25%, usually at least about 50% to 75%, more usually at least about 90% or more is indicative of a differentially expressed gene of interest, i.e., a gene that is underexpressed or down-regulated in the test sample relative to a control sample. Furthermore, a difference in expression level associated with an increase in expression of at least about 25%, usually at least about 50% to 75%, more usually at least about 90% and can be at least about 1½-fold, usually at least about 2-fold to about 10-fold, and can be about 100-fold to about 1,000-fold increase relative to a control sample is indicative of a differentially expressed gene of interest, i.e., an overexpressed or up-regulated gene.

“Differentially expressed polynucleotide” as used herein means a nucleic acid molecule (RNA or DNA) comprising a sequence that represents a differentially expressed gene, e.g., the differentially expressed polynucleotide comprises a sequence (e.g., an open reading frame encoding a gene product) that uniquely identifies a differentially expressed gene so that detection of the differentially expressed polynucleotide in a sample is correlated with the presence of a differentially expressed gene in a sample. “Differentially expressed polynucleotides” is also meant to encompass fragments of the disclosed polynucleotides, e.g., fragments retaining biological activity, as well as nucleic acids homologous, substantially similar, or substantially identical (e.g., having about 90% sequence identity) to the disclosed polynucleotides.

“Diagnosis” as used herein generally includes determination of a subject's susceptibility to a disease or disorder, determination as to whether a subject is presently affected by a disease or disorder, as well as to the prognosis of a subject affected by a disease or disorder (e.g., identification of pre-metastatic or metastatic cancerous states, stages of cancer, or responsiveness of cancer to therapy). The present invention particularly encompasses diagnosis of subjects in the context of breast cancer (e.g., carcinoma in situ (e.g., ductal carcinoma in situ), estrogen receptor (ER)-positive breast cancer, ER-negative breast cancer, or other forms and/or stages of breast cancer), lung cancer (e.g., small cell carcinoma, non-small cell carcinoma, mesothelioma, and other forms and/or stages of lung cancer), and colon cancer (e.g., adenomatous polyp, colorectal carcinoma, and other forms and/or stages of colon cancer).

“Sample” or “biological sample” as used throughout here are generally meant to refer to samples of biological fluids or tissues, particularly samples obtained from tissues, especially from cells of the type associated with the disease for which the diagnostic application is designed (e.g., ductal adenocarcinoma), and the like. “Samples” is also meant to encompass derivatives and fractions of such samples (e.g., cell lysates). Where the sample is solid tissue, the cells of the tissue can be dissociated or tissue sections can be analyzed.

Methods of the subject invention useful in diagnosis or prognosis typically involve comparison of the abundance of a selected differentially expressed gene product in a sample of interest with that of a control to determine any relative differences in the expression of the gene product, where the difference can be measured qualitatively and/or quantitatively. Quantitation can be accomplished, for example, by comparing the level of expression product detected in the sample with the amounts of product present in a standard curve. A comparison can be made visually; by using a technique such as densitometry, with or without computerized assistance; by preparing a representative library of cDNA clones of mRNA isolated from a test sample, sequencing the clones in the library to determine that number of cDNA clones corresponding to the same gene product, and analyzing the number of clones corresponding to that same gene product relative to the number of clones of the same gene product in a control sample; or by using an array to detect relative levels of hybridization to a selected sequence or set of sequences, and comparing the hybridization pattern to that of a control. The differences in expression are then correlated with the presence or absence of an abnormal expression pattern. A variety of different methods for determining the nucleic acid abundance in a sample are known to those of skill in the art (see, e.g., WO 97/27317). In general, diagnostic assays of the invention involve detection of a gene product of a the polynucleotide sequence (e.g., mRNA or polypeptide) that corresponds to a sequence of SEQ ID NOS:1–2707. The patient from whom the sample is obtained can be apparently healthy, susceptible to disease (e.g., as determined by family history or exposure to certain environmental factors), or can already be identified as having a condition in which altered expression of a gene product of the invention is implicated.

Diagnosis can be determined based on detected gene product expression levels of a gene product encoded by at least one, preferably at least two or more, at least 3 or more, or at least 4 or more of the polynucleotides having a sequence set forth in SEQ ID NOS:1–2707, and can involve detection of expression of genes corresponding to all of SEQ ID NOS:1–2707 and/or additional sequences that can serve as additional diagnostic markers and/or reference sequences. Where the diagnostic method is designed to detect the presence or susceptibility of a patient to cancer, the assay preferably involves detection of a gene product encoded by a gene corresponding to a polynucleotide that is differentially expressed in cancer. Examples of such differentially expressed polynucleotides are described in the Examples below. Given the provided polynucleotides and information regarding their relative expression levels provided herein, assays using such polynucleotides and detection of their expression levels in diagnosis and prognosis will be readily apparent to the ordinarily skilled artisan.

Any of a variety of detectable labels can be used in connection with the various embodiments of the diagnostic methods of the invention. Suitable detectable labels include fluorochromes, (e.g. fluorescein isothiocyanate (FITC), rhodamine, Texas Red, phycoerythrin, allophycocyanin, 6-carboxyfluorescein (6-FAM), 2′,7′-dimethoxy-4′,5′-dichloro-6-carboxyfluorescein, 6-carboxy-X-rhodamine (ROX), 6-carboxy-2′,4′,7′,4,7-hexachlorofluorescein (HEX), 5-carboxyfluorescein (5-FAM) or N,N,N′,N′-tetramethyl-6-carboxyrhodamine (TAMRA)), radioactive labels, (e.g. ³²P, ³⁵S, ³H, etc.), and the like. The detectable label can involve a two stage systems (e.g., biotin-avidin, hapten-anti-hapten antibody, etc.)

Reagents specific for the polynucleotides and polypeptides of the invention, such as antibodies and nucleotide probes, can be supplied in a kit for detecting the presence of an expression product in a biological sample. The kit can also contain buffers or labeling components, as well as instructions for using the reagents to detect and quantify expression products in the biological sample. Exemplary embodiments of the diagnostic methods of the invention are described below in more detail.

Polypeptide detection in diagnosis. In one embodiment, the test sample is assayed for the level of a differentially expressed polypeptide. Diagnosis can be accomplished using any of a number of methods to determine the absence or presence or altered amounts of the differentially expressed polypeptide in the test sample. For example, detection can utilize staining of cells or histological sections with labeled antibodies, performed in accordance with conventional methods. Cells can be permeabilized to stain cytoplasmic molecules. In general, antibodies that specifically bind a differentially expressed polypeptide of the invention are added to a sample, and incubated for a period of time sufficient to allow binding to the epitope, usually at least about 10 minutes. The antibody can be detectably labeled for direct detection (e.g., using radioisotopes, enzymes, fluorescers, chemiluminescers, and the like), or can be used in conjunction with a second stage antibody or reagent to detect binding (e.g., biotin with horseradish peroxidase-conjugated avidin, a secondary antibody conjugated to a fluorescent compound, e.g. fluorescein, rhodamine, Texas red, etc.). The absence or presence of antibody binding can be determined by various methods, including flow cytometry of dissociated cells, microscopy, radiography, scintillation counting, etc. Any suitable alternative methods can of qualitative or quantitative detection of levels or amounts of differentially expressed polypeptide can be used, for example ELISA, western blot, immunoprecipitation, radioimmunoassay, etc.

mRNA detection. The diagnostic methods of the invention can also or alternatively involve detection of mRNA encoded by a gene corresponding to a differentially expressed polynucleotides of the invention. Any suitable qualitative or quantitative methods known in the art for detecting specific mRNAs can be used. mRNA can be detected by, for example, in situ hybridization in tissue sections, by reverse transcriptase-PCR, or in Northern blots containing poly A+ mRNA. One of skill in the art can readily use these methods to determine differences in the size or amount of mRNA transcripts between two samples. mRNA expression levels in a sample can also be determined by generation of a library of expressed sequence tags (ESTs) from the sample, where the EST library is representative of sequences present in the sample (Adams, et al., (1991) Science 252:1651). Enumeration of the relative representation of ESTs within the library can be used to approximate the relative representation of the gene transcript within the starting sample. The results of EST analysis of a test sample can then be compared to EST analysis of a reference sample to determine the relative expression levels of a selected polynucleotide, particularly a polynucleotide corresponding to one or more of the differentially expressed genes described herein. Alternatively, gene expression in a test sample can be performed using serial analysis of gene expression (SAGE) methodology (e.g., Velculescu et al., Science (1995) 270:484) or differential display (DD) methodology (see, e.g., U.S. Pat. No. 5,776,683; and U.S. Pat. No. 5,807,680).

Alternatively, gene expression can be analyzed using hybridization analysis. Oligonucleotides or cDNA can be used to selectively identify or capture DNA or RNA of specific sequence composition, and the amount of RNA or cDNA hybridized to a known capture sequence determined qualitatively or quantitatively, to provide information about the relative representation of a particular message within the pool of cellular messages in a sample. Hybridization analysis can be designed to allow for concurrent screening of the relative expression of hundreds to thousands of genes by using, for example, array-based technologies having high density formats, including filters, microscope slides, or microchips, or solution-based technologies that use spectroscopic analysis (e.g., mass spectrometry). One exemplary use of arrays in the diagnostic methods of the invention is described below in more detail.

Use of a single gene in diagnostic applications. The diagnostic methods of the invention can focus on the expression of a single differentially expressed gene. For example, the diagnostic method can involve detecting a differentially expressed gene, or a polymorphism of such a gene (e.g., a polymorphism in an coding region or control region), that is associated with disease. Disease-associated polymorphisms can include deletion or truncation of the gene, mutations that alter expression level and/or affect activity of the encoded protein, etc.

A number of methods are available for analyzing nucleic acids for the presence of a specific sequence, e.g. a disease associated polymorphism. Where large amounts of DNA are available, genomic DNA is used directly. Alternatively, the region of interest is cloned into a suitable vector and grown in sufficient quantity for analysis. Cells that express a differentially expressed genean be used as a source of mRNA, which can be assayed directly or reverse transcribed into cDNA for analysis. The nucleic acid can be amplified by conventional techniques, such as the polymerase chain reaction (PCR), to provide sufficient amounts for analysis, and a detectable label can be included in the amplification reaction (e.g., using a detectably labeled primer or detectably labeled oligonucleotides) to facilitate detection. Alternatively, various methods are also known in the art that utilize oligonucleotide ligation as a means of detecting polymorphisms, see e.g., Riley et al., Nucl. Acids Res. (1990) 18:2887; and Delahunty et al., Am. J. Hum. Genet. (1996) 58:1239.

The amplified or cloned sample nucleic acid can be analyzed by one of a number of methods known in the art. The nucleic acid can be sequenced by dideoxy or other methods, and the sequence of bases compared to a selected sequence, e.g., to a wild-type sequence. Hybridization with the polymorphic or variant sequence can also be used to determine its presence in a sample (e.g., by Southern blot, dot blot, etc.). The hybridization pattern of a polymorphic or variant sequence and a control sequence to an array of oligonucleotide probes immobilized on a solid support, as described in U.S. Pat. No. 5,445,934, or in WO 95/35505, can also be used as a means of identifying polymorphic or variant sequences associated with disease. Single strand conformational polymorphism (SSCP) analysis, denaturing gradient gel electrophoresis (DGGE), and heteroduplex analysis in gel matrices are used to detect conformational changes created by DNA sequence variation as alterations in electrophoretic mobility. Alternatively, where a polymorphism creates or destroys a recognition site for a restriction endonuclease, the sample is digested with that endonuclease, and the products size fractionated to determine whether the fragment was digested. Fractionation is performed by gel or capillary electrophoresis, particularly acrylamide or agarose gels.

Screening for mutations in a gene can be based on the functional or antigenic characteristics of the protein. Protein truncation assays are useful in detecting deletions that can affect the biological activity of the protein. Various immunoassays designed to detect polymorphisms in proteins can be used in screening. Where many diverse genetic mutations lead to a particular disease phenotype, functional protein assays have proven to be effective screening tools. The activity of the encoded protein can be determined by comparison with the wild-type protein.

Pattern matching in diagnosis using arrays. In another embodiment, the diagnostic and/or prognostic methods of the invention involve detection of expression of a selected set of genes in a test sample to produce a test expression pattern (TEP). The TEP is compared to a reference expression pattern (REP), which is generated by detection of expression of the selected set of genes in a reference sample (e.g., a positive or negative control sample). The selected set of genes includes at least one of the genes of the invention, which genes correspond to the polynucleotide sequences of SEQ ID NOS:1–2707. Of particular interest is a selected set of genes that includes gene differentially expressed in the disease for which the test sample is to be screened.

“Reference sequences” or “reference polynucleotides” as used herein in the context of differential gene expression analysis and diagnosis/prognosis refers to a selected set of polynucleotides, which selected set includes at least one or more of the differentially expressed polynucleotides described herein. A plurality of reference sequences, preferably comprising positive and negative control sequences, can be included as reference sequences. Additional suitable reference sequences are found in GenBank, Unigene, and other nucleotide sequence databases (including, e.g., expressed sequence tag (EST), partial, and full-length sequences).

“Reference array” means an array having reference sequences for use in hybridization with a sample, where the reference sequences include all, at least one of, or any subset of the differentially expressed polynucleotides described herein. Usually such an array will include at least 3 different reference sequences, and can include any one or all of the provided differentially expressed sequences. Arrays of interest can further comprise sequences, including polymorphisms, of other genetic sequences, particularly other sequences of interest for screening for a disease or disorder (e.g., cancer, dysplasia, or other related or unrelated diseases, disorders, or conditions). The oligonucleotide sequence on the array will usually be at least about 12 nt in length, and can be of about the length of the provided sequences, or can extend into the flanking regions to generate fragments of 100 nt to 200 nt in length or more. Reference arrays can be produced according to any suitable methods known in the art. For example, methods of producing large arrays of oligonucleotides are described in U.S. Pat. No. 5,134,854, and U.S. Pat. No. 5,445,934 using light-directed synthesis techniques. Using a computer controlled system, a heterogeneous array of monomers is converted, through simultaneous coupling at a number of reaction sites, into a heterogeneous array of polymers. Alternatively, microarrays are generated by deposition of pre-synthesized oligonucleotides onto a solid substrate, for example as described in PCT published application no. WO 95/35505.

A “reference expression pattern” or “REP” as used herein refers to the relative levels of expression of a selected set of genes, particularly of differentially expressed genes, that is associated with a selected cell type, e.g., a normal cell, a cancerous cell, a cell exposed to an environmental stimulus, and the like. A “test expression pattern” or “TEP” refers to relative levels of expression of a selected set of genes, particularly of differentially expressed genes, in a test sample (e.g., a cell of unknown or suspected disease state, from which mRNA is isolated).

REPs can be generated in a variety of ways according to methods well known in the art. For example, REPs can be generated by hybridizing a control sample to an array having a selected set of polynucleotides (particularly a selected set of differentially expressed polynucleotides), acquiring the hybridization data from the array, and storing the data in a format that allows for ready comparison of the REP with a TEP. Alternatively, all expressed sequences in a control sample can be isolated and sequenced, e.g., by isolating mRNA from a control sample, converting the mRNA into cDNA, and sequencing the cDNA. The resulting sequence information roughly or precisely reflects the identity and relative number of expressed sequences in the sample. The sequence information can then be stored in a format (e.g., a computer-readable format) that allows for ready comparison of the REP with a TEP. The REP can be normalized prior to or after data storage, and/or can be processed to selectively remove sequences of expressed genes that are of less interest or that might complicate analysis (e.g., some or all of the sequences associated with housekeeping genes can be eliminated from REP data).

TEPs can be generated in a manner similar to REPs, e.g., by hybridizing a test sample to an array having a selected set of polynucleotides, particularly a selected set of differentially expressed polynucleotides, acquiring the hybridization data from the array, and storing the data in a format that allows for ready comparison of the TEP with a REP. The REP and TEP to be used in a comparison can be generated simultaneously, or the TEP can be compared to previously generated and stored REPs.

In one embodiment of the invention, comparison of a TEP with a REP involves hybridizing a test sample with a reference array, where the reference array has one or more reference sequences for use in hybridization with a sample. The reference sequences include all, at least one of, or any subset of the differentially expressed polynucleotides described herein. Hybridization data for the test sample is acquired, the data normalized, and the produced TEP compared with a REP generated using an array having the same or similar selected set of differentially expressed polynucleotides. Probes that correspond to sequences differentially expressed between the two samples will show decreased or increased hybridization efficiency for one of the samples relative to the other.

Methods for collection of data from hybridization of samples with a reference arrays are well known in the art. For example, the polynucleotides of the reference and test samples can be generated using a detectable fluorescent label, and hybridization of the polynucleotides in the samples detected by scanning the microarrays for the presence of the detectable label using, for example, a microscope and light source for directing light at a substrate. A photon counter detects fluorescence from the substrate, while an x-y translation stage varies the location of the substrate. A confocal detection device that can be used in the subject methods is described in U.S. Pat. No. 5,631,734. A scanning laser microscope is described in Shalon et al., Genome Res. (1996) 6:639. A scan, using the appropriate excitation line, is performed for each fluorophore used. The digital images generated from the scan are then combined for subsequent analysis. For any particular array element, the ratio of the fluorescent signal from one sample (e.g., a test sample) is compared to the fluorescent signal from another sample (e.g., a reference sample), and the relative signal intensity determined.

Methods for analyzing the data collected from hybridization to arrays are well known in the art. For example, where detection of hybridization involves a fluorescent label, data analysis can include the steps of determining fluorescent intensity as a function of substrate position from the data collected, removing outliers, i.e. data deviating from a predetermined statistical distribution, and calculating the relative binding affinity of the targets from the remaining data. The resulting data can be displayed as an image with the intensity in each region varying according to the binding affinity between targets and probes.

In general, the test sample is classified as having a gene expression profile corresponding to that associated with a disease or non-disease state by comparing the TEP generated from the test sample to one or more REPs generated from reference samples (e.g., from samples associated with cancer or specific stages of cancer, dysplasia, samples affected by a disease other than cancer, normal samples, etc.). The criteria for a match or a substantial match between a TEP and a REP include expression of the same or substantially the same set of reference genes, as well as expression of these reference genes at substantially the same levels (e.g., no significant difference between the samples for a signal associated with a selected reference sequence after normalization of the samples, or at least no greater than about 25% to about 40% difference in signal strength for a given reference sequence. In general, a pattern match between a TEP and a REP includes a match in expression, preferably a match in qualitative or quantitative expression level, of at least one of, all or any subset of the differentially expressed genes of the invention.

Pattern matching can be performed manually, or can be performed using a computer program. Methods for preparation of substrate matrices (e.g., arrays), design of oligonucleotides for use with such matrices, labeling of probes, hybridization conditions, scanning of hybridized matrices, and analysis of patterns generated, including comparison analysis, are described in, for example, U.S. Pat. No. 5,800,992.

Diagnosis Prognosis and Management of Cancer

The polynucleotides of the invention and their gene products are of particular interest as genetic or biochemical markers (e.g., in blood or tissues) that will detect the earliest changes along the carcinogenesis pathway and/or to monitor the efficacy of various therapies and preventive interventions. For example, the level of expression of certain polynucleotides can be indicative of a poorer prognosis, and therefore warrant more aggressive chemo- or radio-therapy for a patient or vice versa. The correlation of novel surrogate tumor specific features with response to treatment and outcome in patients can define prognostic indicators that allow the design of tailored therapy based on the molecular profile of the tumor. These therapies include antibody targeting and gene therapy. Determining expression of certain polynucleotides and comparison of a patients profile with known expression in normal tissue and variants of the disease allows a determination of the best possible treatment for a patient, both in terms of specificity of treatment and in terms of comfort level of the patient. Surrogate tumor markers, such as polynucleotide expression, can also be used to better classify, and thus diagnose and treat, different forms and disease states of cancer. Two classifications widely used in oncology that can benefit from identification of the expression levels of the polynucleotides of the invention are staging of the cancerous disorder, and grading the nature of the cancerous tissue.

The polynucleotides of the invention can be useful to monitor patients having or susceptible to cancer to detect potentially malignant events at a molecular level before they are detectable at a gross morphological level. Furthermore, a polynucleotide of the invention identified as important for one type of cancer can also have implications for development or risk of development of other types of cancer, e.g., where a polynucleotide is differentially expressed across various cancer types. Thus, for example, expression of a polynucleotide that has clinical implications for metastatic colon cancer can also have clinical implications for stomach cancer or endometrial cancer.

Staging. Staging is a process used by physicians to describe how advanced the cancerous state is in a patient. Staging assists the physician in determining a prognosis, planning treatment and evaluating the results of such treatment. Staging systems vary with the types of cancer, but generally involve the following “TNM” system: the type of tumor, indicated by T; whether the cancer has metastasized to nearby lymph nodes, indicated by N; and whether the cancer has metastasized to more distant parts of the body, indicated by M. Generally, if a cancer is only detectable in the area of the primary lesion without having spread to any lymph nodes it is called Stage I. If it has spread only to the closest lymph nodes, it is called Stage II. In Stage III, the cancer has generally spread to the lymph nodes in near proximity to the site of the primary lesion. Cancers that have spread to a distant part of the body, such as the liver, bone, brain or other site, are Stage IV, the most advanced stage.

The polynucleotides of the invention can facilitate fine-tuning of the staging process by identifying markers for the aggresivity of a cancer, e.g. the metastatic potential, as well as the presence in different areas of the body. Thus, a Stage II cancer with a polynucleotide signifying a high metastatic potential cancer can be used to change a borderline Stage II tumor to a Stage III tumor, justifying more aggressive therapy. Conversely, the presence of a polynucleotide signifying a lower metastatic potential allows more conservative staging of a tumor.

Grading of cancers. Grade is a term used to describe how closely a tumor resembles normal tissue of its same type. The microscopic appearance of a tumor is used to identify tumor grade based on parameters such as cell morphology, cellular organization, and other markers of differentiation. As a general rule, the grade of a tumor corresponds to its rate of growth or aggressiveness, with undifferentiated or high-grade tumors being more aggressive than well differentiated or low-grade tumors. The following guidelines are generally used for grading tumors: 1) GX Grade cannot be assessed; 2) G1 Well differentiated; G2 Moderately well differentiated; 3) G3 Poorly differentiated; 4) G4 Undifferentiated. The polynucleotides of the invention can be especially valuable in determining the grade of the tumor, as they not only can aid in determining the differentiation status of the cells of a tumor, they can also identify factors other than differentiation that are valuable in determining the aggressiveness of a tumor, such as metastatic potential.

Detection of lung cancer. The polynucleotides of the invention can be used to detect lung cancer in a subject. Although there are more than a dozen different kinds of lung cancer, the two main types of lung cancer are small cell and nonsmall cell, which encompass about 90% of all lung cancer cases. Small cell carcinoma (also called oat cell carcinoma) usually starts in one of the larger bronchial tubes, grows fairly rapidly, and is likely to be large by the time of diagnosis. Nonsmall cell lung cancer (NSCLC) is made up of three general subtypes of lung cancer. Epidermoid carcinoma (also called squamous cell carcinoma) usually starts in one of the larger bronchial tubes and grows relatively slowly. The size of these tumors can range from very small to quite large. Adenocarcinoma starts growing near the outside surface of the lung and can vary in both size and growth rate. Some slowly growing adenocarcinomas are described as alveolar cell cancer. Large cell carcinoma starts near the surface of the lung, grows rapidly, and the growth is usually fairly large when diagnosed. Other less common forms of lung cancer are carcinoid, cylindroma, mucoepidermoid, and malignant mesothelioma.

The polynucleotides of the invention, e.g., polynucleotides differentially expressed in normal cells versus cancerous lung cells (e.g., tumor cells of high or low metastatic potential) or between types of cancerous lung cells (e.g., high metastatic versus low metastatic), can be used to distinguish types of lung cancer as well as identifying traits specific to a certain patient's cancer and selecting an appropriate therapy. For example, if the patient's biopsy expresses a polynucleotide that is associated with a low metastatic potential, it may justify leaving a larger portion of the patient's lung in surgery to remove the lesion. Alternatively, a smaller lesion with expression of a polynucleotide that is associated with high metastatic potential may justify a more radical removal of lung tissue and/or the surrounding lymph nodes, even if no metastasis can be identified through pathological examination.

Detection of breast cancer. The majority of breast cancers are adenocarcinomas subtypes, which can be summarized as follows: 1) ductal carcinoma in situ (DCIS), including comedocarcinoma; 2) infiltrating (or invasive) ductal carcinoma (IDC); 3) lobular carcinoma in situ (LCIS); 4) infiltrating (or invasive) lobular carcinoma (ILC); 5) inflammatory breast cancer; 6) medullary carcinoma; 7) mucinous carcinoma; 8) Paget's disease of the nipple; 9) Phyllodes tumor; and 10) tubular carcinoma;

The expression of polynucleotides of the invention can be used in the diagnosis and management of breast cancer, as well as to distinguish between types of breast cancer. Detection of breast cancer can be determined using expression levels of any of the appropriate polynucleotides of the invention, either alone or in combination. Determination of the aggressive nature and/or the metastatic potential of a breast cancer can also be determined by comparing levels of one or more polynucleotides of the invention and comparing levels of another sequence known to vary in cancerous tissue, e.g. ER expression. In addition, development of breast cancer can be detected by examining the ratio of expression of a differentially expressed polynucleotide to the levels of steroid hormones (e.g., testosterone or estrogen) or to other hormones (e.g., growth hormone, insulin). Thus expression of specific marker polynucleotides can be used to discriminate between normal and cancerous breast tissue, to discriminate between breast cancers with different cells of origin, to discriminate between breast cancers with different potential metastatic rates, etc.

Detection of colon cancer. The polynucleotides of the invention exhibiting the appropriate expression pattern can be used to detect colon cancer in a subject. Colorectal cancer is one of the most common neoplasms in humans and perhaps the most frequent form of hereditary neoplasia. Prevention and early detection are key factors in controlling and curing colorectal cancer. Colorectal cancer begins as polyps, which are small, benign growths of cells that form on the inner lining of the colon. Over a period of several years, some of these polyps accumulate additional mutations and become cancerous. Multiple familial colorectal cancer disorders have been identified, which are summarized as follows: 1) Familial adenomatous polyposis (FAP); 2) Gardner's syndrome; 3) Hereditary nonpolyposis colon cancer (HNPCC); and 4) Familial colorectal cancer in Ashkenazi Jews. The expression of appropriate polynucleotides of the invention can be used in the diagnosis, prognosis and management of colorectal cancer. Detection of colon cancer can be determined using expression levels of any of these sequences alone or in combination with the levels of expression. Determination of the aggressive nature and/or the metastatic potential of a colon cancer can be determined by comparing levels of one or more polynucleotides of the invention and comparing total levels of another sequence known to vary in cancerous tissue, e.g., expression of p53, DCC ras, lor FAP (see, e.g., Fearon E R, et al., Cell (1990) 61(5):759; Hamilton S R et al., Cancer (1993) 72:957; Bodmer W, et al., Nat Genet. (1994) 4(3):217; Fearon E R, Ann N Y Acad Sci. (1995) 768:101). For example, development of colon cancer can be detected by examining the ratio of any of the polynucleotides of the invention to the levels of oncogenes (e.g. ras) or tumor suppressor genes (e.g. FAP or p53). Thus expression of specific marker polynucleotides can be used to discriminate between normal and cancerous colon tissue, to discriminate between colon cancers with different cells of origin, to discriminate between colon cancers with different potential metastatic rates, etc.

Use of Polynucleotides to Screen for Peptide Analogs and Antagonists

Polypeptides encoded by the instant polynucleotides and corresponding full length genes can be used to screen peptide libraries to identify binding partners, such as receptors, from among the encoded polypeptides. Peptide libraries can be synthesized according to methods known in the art (see, e.g., U.S. Pat. No. 5,010,175, and WO 91/17823). Agonists or antagonists of the polypeptides if the invention can be screened using any available method known in the art, such as signal transduction, antibody binding, receptor binding, mitogenic assays, chemotaxis assays, etc. The assay conditions ideally should resemble the conditions under which the native activity is exhibited in vivo, that is, under physiologic pH, temperature, and ionic strength. Suitable agonists or antagonists will exhibit strong inhibition or enhancement of the native activity at concentrations that do not cause toxic side effects in the subject. Agonists or antagonists that compete for binding to the native polypeptide can require concentrations equal to or greater than the native concentration, while inhibitors capable of binding irreversibly to the polypeptide can be added in concentrations on the order of the native concentration.

Such screening and experimentation can lead to identification of a novel polypeptide binding partner, such as a receptor, encoded by a gene or a cDNA corresponding to a polynucleotide of the invention, and at least one peptide agonist or antagonist of the novel binding partner. Such agonists and antagonists can be used to modulate, enhance, or inhibit receptor function in cells to which the receptor is native, or in cells that possess the receptor as a result of genetic engineering. Further, if the novel receptor shares biologically important characteristics with a known receptor, information about agonist/antagonist binding can facilitate development of improved agonists/antagonists of the known receptor.

Pharmaceutical Compositions and Therapeutic Uses

Pharmaceutical compositions of the invention can comprise polypeptides, antibodies, or polynucleotides (including antisense nucleotides and ribozymes) of the claimed invention in a therapeutically effective amount. The term “therapeutically effective amount” as used herein refers to an amount of a therapeutic agent to treat, ameliorate, or prevent a desired disease or condition, or to exhibit a detectable therapeutic or preventative effect. The effect can be detected by, for example, chemical markers or antigen levels. Therapeutic effects also include reduction in physical symptoms, such as decreased body temperature. The precise effective amount for a subject will depend upon the subject's size and health, the nature and extent of the condition, and the therapeutics or combination of therapeutics selected for administration. Thus, it is not useful to specify an exact effective amount in advance. However, the effective amount for a given situation is determined by routine experimentation and is within the judgment of the clinician. For purposes of the present invention, an effective dose will generally be from about 0.01 mg/kg to 50 mg/kg or 0.05 mg/kg to about 10 mg/kg of the DNA constructs in the individual to which it is administered.

A pharmaceutical composition can also contain a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier” refers to a carrier for administration of a therapeutic agent, such as antibodies or a polypeptide, genes, and other therapeutic agents. The term refers to any pharmaceutical carrier that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which can be administered without undue toxicity. Suitable carriers can be large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactive virus particles. Such carriers are well known to those of ordinary skill in the art. Pharmaceutically acceptable carriers in therapeutic compositions can include liquids such as water, saline, glycerol and ethanol. Auxiliary substances, such as wetting or emulsifying agents, pH buffering substances, and the like, can also be present in such vehicles. Typically, the therapeutic compositions are prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection can also be prepared. Liposomes are included within the definition of a pharmaceutically acceptable carrier. Pharmaceutically acceptable salts can also be present in the pharmaceutical composition, e.g., mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and the like; and the salts of organic acids such as acetates, propionates, malonates, benzoates, and the like. A thorough discussion of pharmaceutically acceptable excipients is available in Remington 's Pharmaceutical Sciences (Mack Pub. Co., N.J. 1991).

Delivery Methods. Once formulated, the compositions of the invention can be (1) administered directly to the subject (e.g., as polynucleotide or polypeptides); or (2) delivered ex vivo, to cells derived from the subject (e.g., as in ex vivo gene therapy). Direct delivery of the compositions will generally be accomplished by parenteral injection, e.g., subcutaneously, intraperitoneally, intravenously or intramuscularly, intratumoral or to the interstitial space of a tissue. Other modes of administration include oral and pulmonary administration, suppositories, and transdermal applications, needles, and gene guns or hyposprays. Dosage treatment can be a single dose schedule or a multiple dose schedule.

Methods for the ex vivo delivery and reimplantation of transformed cells into a subject are known in the art and described in e.g., International Publication No. WO 93/14778. Examples of cells useful in ex vivo applications include, for example, stem cells, particularly hematopoetic, lymph cells, macrophages, dendritic cells, or tumor cells. Generally, delivery of nucleic acids for both ex vivo and in vitro applications can be accomplished by, for example, dextran-mediated transfection, calcium phosphate precipitation, polybrene mediated transfection, protoplast fusion, electroporation, encapsulation of the polynucleotide(s) in liposomes, and direct microinjection of the DNA into nuclei, all well known in the art.

Once a gene corresponding to a polynucleotide of the invention has been found to correlate with a proliferative disorder, such as neoplasia, dysplasia, and hyperplasia, the disorder can be amenable to treatment by administration of a therapeutic agent based on the provided polynucleotide, corresponding polypeptide or other corresponding molecule (e.g., antisense, ribozyme, etc.).

The dose and the means of administration of the inventive pharmaceutical compositions are determined based on the specific qualities of the therapeutic composition, the condition, age, and weight of the patient, the progression of the disease, and other relevant factors. For example, administration of polynucleotide therapeutic compositions agents of the invention includes local or systemic administration, including injection, oral administration, particle gun or catheterized administration, and topical administration. Preferably, the therapeutic polynucleotide composition contains an expression construct comprising a promoter operably linked to a polynucleotide of at least 12, 22, 25, 30, or 35 contiguous nt of the polynucleotide disclosed herein. Various methods can be used to administer the therapeutic composition directly to a specific site in the body. For example, a small metastatic lesion is located and the therapeutic composition injected several times in several different locations within the body of tumor. Alternatively, arteries which serve a tumor are identified, and the therapeutic composition injected into such an artery, in order to deliver the composition directly into the tumor. A tumor that has a necrotic center is aspirated and the composition injected directly into the now empty center of the tumor. The antisense composition is directly administered to the surface of the tumor, for example, by topical application of the composition. X-ray imaging is used to assist in certain of the above delivery methods.

Receptor-mediated targeted delivery of therapeutic compositions containing an antisense polynucleotide, subgenomic polynucleotides, or antibodies to specific tissues can also be used. Receptor-mediated DNA delivery techniques are described in, for example, Findeis et al., Trends Biotechnol. (1993) 11:202; Chiou et al., Gene Therapeutics: Methods And Applications Of Direct Gene Transfer (J. A. Wolff, ed.) (1994); Wu et al., J. Biol. Chem. (1988) 263:621; Wu et al., J. Biol. Chem. (1994) 269:542; Zenke et al., Proc. Natl. Acad. Sci. (USA) (1990) 87:3655; Wu et al., J. Biol. Chem. (1991) 266:338. Therapeutic compositions containing a polynucleotide are administered in a range of about 100 ng to about 200 mg of DNA for local administration in a gene therapy protocol. Concentration ranges of about 500 ng to about 50 mg, about 1 g to about 2 mg, about 5 g to about 500 g, and about 20 g to about 100 g of DNA can also be used during a gene therapy protocol. Factors such as method of action (e.g., for enhancing or inhibiting levels of the encoded gene product) and efficacy of transformation and expression are considerations which will affect the dosage required for ultimate efficacy of the antisense subgenomic polynucleotides. Where greater expression is desired over a larger area of tissue, larger amounts of antisense subgenomic polynucleotides or the same amounts readministered in a successive protocol of administrations, or several administrations to different adjacent or close tissue portions of, for example, a tumor site, may be required to effect a positive therapeutic outcome. In all cases, routine experimentation in clinical trials will determine specific ranges for optimal therapeutic effect. For polynucleotide-related genes encoding polypeptides or proteins with anti-inflammatory activity, suitable use, doses, and administration are described in U.S. Pat. No. 5,654,173.

The therapeutic polynucleotides and polypeptides of the present invention can be delivered using gene delivery vehicles. The gene delivery vehicle can be of viral or non-viral origin (see generally, Jolly, Cancer Gene Therapy (1994) 1:51; Kimura, Human Gene Therapy (1994) 5:845; Connelly, Human Gene Therapy (1995) 1:185; and Kaplitt, Nature Genetics (1994) 6:148). Expression of such coding sequences can be induced using endogenous mammalian or heterologous promoters. Expression of the coding sequence can be either constitutive or regulated.

Viral-based vectors for delivery of a desired polynucleotide and expression in a desired cell are well known in the art. Exemplary viral-based vehicles include, but are not limited to, recombinant retroviruses (see, e.g., WO 90/07936; WO 94/03622; WO 93/25698; WO 93/25234; U.S. Pat. No. 5,219,740; WO 93/11230; WO 93/10218; U.S. Pat. No. 4,777,127; GB Patent No. 2,200,651; EP 0 345 242; and WO 91/02805), alphavirus-based vectors (e.g., Sindbis virus vectors, Semliki forest virus (ATCC VR-67; ATCC VR-1247), Ross River virus (ATCC VR-373; ATCC VR-1246) and Venezuelan equine encephalitis virus (ATCC VR-923; ATCC VR-1250; ATCC VR 1249; ATCC VR-532), and adeno-associated virus (AAV) vectors (see, e.g., WO 94/12649, WO 93/03769; WO 93/19191; WO 94/28938; WO 95/11984 and WO 95/00655). Administration of DNA linked to killed adenovirus as described in Curiel, Hum. Gene Ther. (1992) 3:147 can also be employed.

Non-viral delivery vehicles and methods can also be employed, including, but not limited to, polycationic condensed DNA linked or unlinked to killed adenovirus alone (see, e.g., Curiel, Hum. Gene Ther. (1992) 3:147); ligand-linked DNA (see, e.g., Wu, J. Biol. Chem. (1989) 264:16985); eukaryotic cell delivery vehicles cells (see, e.g., U.S. Pat. No. 5,814,482; WO 95/07994; WO 96/17072; WO 95/30763; and WO 97/42338) and nucleic charge neutralization or fusion with cell membranes. Naked DNA can also be employed. Exemplary naked DNA introduction methods are described in WO 90/11092 and U.S. Pat. No. 5,580,859. Liposomes that can act as gene delivery vehicles are described in U.S. Pat. No. 5,422,120; WO 95/13796; WO 94/23697; WO 91/14445; and EP 0524968. Additional approaches are described in Philip, Mol. Cell Biol. (1994) 14:2411, and in Woffendin, Proc. Natl. Acad. Sci. (1994) 91:1581

Further non-viral delivery suitable for use includes mechanical delivery systems such as the approach described in Woffendin et al., Proc. Natl. Acad. Sci. USA (1994) 91(24):11581. Moreover, the coding sequence and the product of expression of such can be delivered through deposition of photopolymerized hydrogel materials or use of ionizing radiation (see, e.g., U.S. Pat. No. 5,206,152 and WO 92/11033). Other conventional methods for gene delivery that can be used for delivery of the coding sequence include, for example, use of hand-held gene transfer particle gun (see, e.g., U.S. Pat. No. 5,149,655); use of ionizing radiation for activating transferred gene (see, e.g., U.S. Pat. No. 5,206,152 and WO 92/11033).

The present invention will now be illustrated by reference to the following examples which set forth particularly advantageous embodiments. However, it should be noted that these embodiments are illustrative and are not to be construed as restricting the invention in any way.

EXAMPLES Example 1 Source of Biological Materials and Overview of Novel Polynucleotides Expressed by the Biological Materials

cDNA libraries were constructed from either human colon cancer cell line Km12L4-A (Morikawa, et al., Cancer Research (1988) 48:6863), KM12C (Morikawa et al. Cancer Res. (1988) 48:1943–1948), or MDA-MB-231 (Brinkley et al. Cancer Res. (1980) 40:3118–3129) was used to construct a cDNA library from mRNA isolated from the cells. Sequences expressed by these cell lines were isolated and analyzed; most sequences were about 275–300 nucleotides in length. The KM12L4-A cell line is derived from the KM12C cell line. The KM12C cell line, which is poorly metastatic (low metastatic) was established in culture from a Dukes' stage B₂ surgical specimen (Morikawa et al. Cancer Res. (1988) 48:6863). The KML4-A is a highly metastatic subline derived from KM12C (Yeatman et al. Nucl. Acids. Res. (1995) 23:4007; Bao-Ling et al. Proc. Annu. Meet. Am. Assoc. Cancer. Res. (1995) 21:3269). The KM12C and KM12C-derived cell lines (e.g., KM12L4, KM12L4-A, etc.) are well-recognized in the art as a model cell line for the study of colon cancer (see, e.g., Moriakawa et al., supra; Radinsky et al. Clin. Cancer Res. (1995) 1:19; Yeatman et al., (1995) supra; Yeatman et al. Clin. Exp. Metastasis (1996) 14:246). The MDA-MB-231 cell line was originally isolated from pleural effusions (Cailleau, J. Natl. Cancer. Inst. (1974) 53:661), is of high metastatic potential, and forms poorly differentiated adenocarcinoma grade II in nude mice consistent with breast carcinoma.

The sequences of the isolated polynucleotides were first masked to eliminate low complexity sequences using the XBLAST masking program (Claverie “Effective Large-Scale Sequence Similarity Searches,” In: Computer Methods for Macromolecular Sequence Analysis, Doolittle, ed., Meth. Enzymol. 266:212–227 Academic Press, NY, N.Y. (1996); see particularly Claverie, in “Automated DNA Sequencing and Analysis Techniques” Adams et al., eds., Chap. 36, p. 267 Academic Press, San Diego, 1994 and Claverie et al. Comput. Chem. (1993) 17:191). Generally, masking does not influence the final search results, except to eliminate sequences of relative little interest due to their low complexity, and to eliminate multiple “hits” based on similarity to repetitive regions common to multiple sequences, e.g., Alu repeats. Masking resulted in the elimination of 43 sequences. The remaining sequences were then used in a BLASTN vs. GenBank search; sequences that exhibited greater than 70% overlap, 99% identity, and a p value of less than 1×10⁻⁴⁰ were discarded. Sequences from this search also were discarded if the inclusive parameters were met, but the sequence was ribosomal or vector-derived.

The resulting sequences from the previous search were classified into three groups (1, 2 and 3 below) and searched in a BLASTX vs. NRP (non-redundant proteins) database search: (1) unknown (no hits in the GenBank search), (2) weak similarity (greater than 45% identity and p value of less than 1×10⁻⁵), and (3) high similarity (greater than 60% overlap, greater than 80% identity, and p value less than 1×10⁻⁵). Sequences having greater than 70% overlap, greater than 99% identity, and p value of less than 1×10⁻⁴⁰ were discarded.

The remaining sequences were classified as unknown (no hits), weak similarity, and high similarity (parameters as above). Two searches were performed on these sequences. First, a BLAST vs. EST database search was performed and sequences with greater than 99% overlap, greater than 99% similarity and a p value of less than 1×10⁻⁴⁰ were discarded. Sequences with a p value of less than 1×10⁻⁶⁵ when compared to a database sequence of human origin were also excluded. Second, a BLASTN vs. Patent GeneSeq database was performed and sequences having greater than 99% identity, p value less than 1×10⁻⁴⁰, and greater than 99% overlap were discarded.

The remaining sequences were subjected to screening using other rules and redundancies in the dataset. Sequences with a p value of less than 1×10⁻¹¹¹ in relation to a database sequence of human origin were specifically excluded. The final result provided the 1,565 sequences listed as SEQ ID NOS:1–1565 in the accompanying Sequence Listing and summarized in Table 1A (inserted prior to claims). Each identified polynucleotide represents sequence from at least a partial mRNA transcript.

Table 1A provides: 1) the SEQ ID NO assigned to each sequence for use in the present specification; 2) the filing date of the U.S. priority application in which the sequence was first filed; 3) the attorney docket number assigned to the priority application (for internal use); 4) the SEQ ID NO assigned to the sequence in the priority application; 5) the sequence name used as an internal identifier of the sequence; and 6) the name assigned to the clone from which the sequence was isolated. Because the provided polynucleotides represent partial mRNA transcripts, two or more polynucleotides of the invention may represent different regions of the same mRNA transcript and the same gene. Thus, if two or more SEQ ID NOS: are identified as belonging to the same clone, then either sequence can be used to obtain the full-length mRNA or gene.

In order to confirm the sequences of SEQ ID NOS:1–1565, the clones were retrieved from a library using a robotic retrieval system, and the inserts of the retrieved clones re-sequenced. These “validation” sequences are provided as SEQ ID NOS:1566–2610 in the Sequence Listing, and a summary of the “validation” sequences provided in Table 1B (inserted prior to claims). Table 1B provides: 1) the SEQ ID NO assigned to each sequence for use in the present specification; 2) the sequence name assigned to the “validation” sequence obtained; 3) whether the “validation” sequence contains sequence that overlaps with an original sequence of SEQ ID NOS:1–1565 (Validation Overlap (VO)), or whether the “validation” sequence does not substantially overlap with an original sequence of SEQ ID NOS:1–1565 (indicated by Validation Non-Overlap (VNO)); and 4) where the sequence is indicated as VO, the name of the clone that contains the indicated “validation” sequence. “Validation” sequences are indicated as “VO” where the “validation” sequence overlaps with an original sequence (e.g., one of SEQ ID NOS:1–1565), and/or the “validation” sequence belongs to the same cluster as the original sequence using the clustering technique described above. Because the inserts of the clones are generally longer than the original sequence and the validation sequence, it is possible that a “validation” sequence can be obtained from the same clone as an original sequence but yet not share any of the sequence of the original. Such validation sequences will, however, belong to the same cluster as the original sequence using the clustering technique described above. VO “validation” sequences are contained within the same clone as the original sequence (one of SEQ ID NOS:1–1565). “Validation” sequences that provided overlapping sequence are indicating by “VO” can be correlated with the original sequences they validate by referring to Table 1A. Sequences indicated as VNO are treated as newly isolated sequences and may or may not be related to the sequences of SEQ ID NOS:1–1565. Because the “validation” sequences are often longer than the original polynucleotide sequences and thus provide additional sequence information. All validation sequences can be obtained either from an indicated clone (e.g., for VO sequences) or from a cDNA library described herein (e.g., using primers designed from the sequence provided in the sequence listing).

Example 2 Results of Public Database Search to Identify Function of Gene Products

SEQ ID NOS:1566–2610 were translated in all three reading frames, and the nucleotide sequences and translated amino acid sequences used as query sequences to search for homologous sequences in either the GenBank (nucleotide sequences) or Non-Redundant Protein (amino acid sequences) databases. Query and individual sequences were aligned using the BLAST 2.0 programs, available over the world wide web at ncbi.nlm.nih.gov/BLAST (see also Altschul, et al. Nucleic Acids Res. (1997) 25:3389–3402). The sequences were masked to various extents to prevent searching of repetitive sequences or poly-A sequences, using the XBLAST program for masking low complexity as described above in Example 1.

Tables 2A and 2B (inserted before the claims) provide the alignment summaries having a p value of 1×10⁻² or less indicating substantial homology between the sequences of the present invention and those of the indicated public databases. Table 2A provides the SEQ ID NO of the query sequence, the accession number of the GenBank database entry of the homologous sequence, and the p value of the alignment. Table 2A provides the SEQ ID NO of the query sequence, the accession number of the Non-Redundant Protein database entry of the homologous sequence, and the p value of the alignment. The alignments provided in Tables 2A and 2B are the best available alignment to a DNA or amino acid sequence at a time just prior to filing of the present specification. The activity of the polypeptide encoded by the SEQ ID NOS listed in Tables 2A and 2B can be extrapolated to be substantially the same or substantially similar to the activity of the reported nearest neighbor or closely related sequence. The accession number of the nearest neighbor is reported, providing a publicly available reference to the activities and functions exhibited by the nearest neighbor. The public information regarding the activities and functions of each of the nearest neighbor sequences is incorporated by reference in this application. Also incorporated by reference is all publicly available information regarding the sequence, as well as the putative and actual activities and functions of the nearest neighbor sequences listed in Table 2 and their related sequences. The search program and database used for the alignment, as well as the calculation of the p value are also indicated.

Full length sequences or fragments of the polynucleotide sequences of the nearest neighbors can be used as probes and primers to identify and isolate the full length sequence of the corresponding polynucleotide. The nearest neighbors can indicate a tissue or cell type to be used to construct a library for the full-length sequences of the corresponding polynucleotides.

Example 3 Members of Protein Families

SEQ ID NOS:1566–2601 were used to conduct a profile search as described in the specification above. Several of the polynucleotides of the invention were found to encode polypeptides having characteristics of a polypeptide belonging to a known protein family (and thus represent new members of these protein families) and/or comprising a known functional domain (Table 3A, inserted prior to claims). Table 3A provides the SEQ ID NO: of the query sequence, a brief description of the profile hit, the position of the query sequence within the individual sequence (indicated as “start” and “stop”), and the orientation (Direction) of the query sequence with respect to the individual sequence, where forward (for) indicates that the alignment is in the same direction (left to right) as the sequence provided in the Sequence Listing and reverse (rev) indicates that the alignment is with a sequence complementary to the sequence provided in the Sequence Listing.

Some polynucleotides exhibited multiple profile hits where the query sequence contains overlapping profile regions, and/or where the sequence contains two different functional domains. Each of the profile hits of Table 3A are described in more detail below. The acronyms for the profiles (provided in parentheses) are those used to identify the profile in the Pfam and Prosite databases. The Pfam database can be accessed through any of the following URLS: pfam.wustl.edu/index; sanger.ac.uk/Software/Pfam; and cgr.ki.se/Pfam. The Prosite database can be accessed at expasy.ch/prosite. The public information available on the Pfam and Prosite databases regarding the various profiles, including but not limited to the activities, function, and consensus sequences of various proteins families and protein domains, is incorporated herein by reference.

14-3-3 Family (14 3 3). SEQ ID NO:1967 corresponds to a sequence encoding a 14-3-3 protein family member. The 14-3-3 protein family includes a group of closely related acidic homodimeric proteins of about 30 kD first identified as very abundant in mammalian brain tissues and located preferentially in neurons (Aitken et al. Trends Biochem. Sci. (1995) 20:95–97; Morrison Science (1994) 266:56–57; and Xiao et al. Nature (1995) 376:188–191). The 14-3-3 proteins have multiple biological activities, including a key role in signal transduction pathways and the cell cycle. 14-3-3 proteins interact with kinases (e.g., PKC or Raf-1), and can also function as protein-kinase dependent activators of tyrosine and tryptophan hydroxylases. The 14-3-3 protein sequences are extremely well conserved, and include two highly conserved regions: the first is a peptide of 11 residues located in the N-terminal section; the second, a 20 amino acid region located in the C-terminal section. The consensus patterns are as follows: 1) R-N-L-[LIV]-S-[VG]-[GA]-Y-[KN]-N-[IVA]; 2) Y-K-[DE]-S-T-L-I-[IM]-Q-L-[LF]-[RHC]-D-N-[LF]-T-[LS]-W-[TAN]-[SAD].

3′5′-Cyclin Nucleotide Phosphodiesterases (PDEase). SEQ ID NO: 2366 represents a polynucleotide encoding a novel 3′5′-cyclic nucleotide phosphodiesterase. PDEases catalyze the hydrolysis of cAMP or cGMP to the corresponding nucleoside 5′ monophosphates (Charbonneau et al, Proc. Natl. Acad. Sci. U.S.A. (1986) 83:9308). There are at least seven different subfamilies of PDEases (Beavo et al., Trends Pharmacol. Sci. (1990) 11:150; http://weber.u.washington.edu/˜pde/: 1) Type 1, calmodulin/calcium-dependent PDEases; 2) Type 2, cGMP-stimulated PDEases; 3) Type 3, cGMP-inhibited PDEases; 4) Type 4, cAMP-specific PDEases.; 5) Type 5, cGMP-specific PDEases; 6) Type 6, rhodopsin-sensitive cGMP-specific PDEases; and 7) Type 7, High affinity cAMP-specific PDEases. All PDEase forms share a conserved domain of about 270 residues. The signature pattern is determined from a stretch of 12 residues that contains two conserved histidines: H-D-[LIVMFY]-x-H-x-[AG]-x(2)-[NQ]-x-[LIVMFY].

Four Transmembrane Integral Membrane Proteins (transmembrane4). SEQ ID NOS:1579 and 1978 sequences correspond to a sequence encoding a member of the four transmembrane segments integral membrane protein family (tm4 family). The tm4 family of proteins includes a number of evolutionarily-related eukaryotic cell surface antigens (Levy et al., J. Biol. Chem., (1991) 266:14597; Tomlinson et al., Eur. J. Immunol. (1993) 23:136; Barclay et al. The leucocyte antigen factbooks. (1993) Academic Press, London/San Diego). The tm4 family members are type III membrane proteins, which are integral membrane proteins containing an N-terminal membrane-anchoring domain that functions both as a translocation signal and as a membrane anchor. The family members also contain three additional transmembrane regions, at least seven conserved cysteines residues, and are of approximately the same size (218 to 284 residues). The consensus pattern spans a conserved region including two cysteines located in a short cytoplasmic loop between two transmembrane domains: Consensus pattern: G-x(3)-[LIVMF]-x(2)-[GSA]-[LIVMF](2)-G-C-x-[GA]-[STA]-x(2)-[EG]-x(2)-[CWN]-[LIVM](2).

Seven Transmembrane Integral Membrane Proteins—Rhodopsin Family (7tm 1). SEQ ID NOS:1652, 1927, and 2068 correspond to a sequence encoding a member of the seven transmembrane (7tm) receptor rhodopsin family. G-protein coupled receptors of the (7tm) rhodopsin family include hormones, neurotransmitters, and light receptors that transduce extracellular signals by interaction with guanine nucleotide-binding (G) proteins (Strosberg Eur. J. Biochem. (1991) 196:1, Kerlavage Curr. Opin. Struct. Biol. (1991) 1:394, Probst, et al., DNA Cell Biol. (1992) 11:1, Savarese, et al., Biochem. J. (1992) 283:1, gcrdb.uthscsa.edu, swift.embl-heidelberg.de/7tm) The consensus pattern that contains the conserved triplet and that also spans the major part of the third transmembrane helix is used to detect this widespread family of proteins: [GSTALIVMFYWC]-[GSTANCPDE]-{EDPKRH}-x(2)-[LIVMNQGA]-x(2)-[LIVMFT]-[GSTANC]-[LIVMFYWSTAC]-[DENH]-R-[FYWCSH]-x(2)-[LIVM].

Seven Transmembrane Integral Membrane Proteins—Secretin Family (7tm 2). SEQ ID NOS:1598, 1719, 1911, 1927, 2068, and 2341 correspond to a sequence encoding a member of the seven transmembrane receptor (7tm) secretin family (Jueppner et al. Science (1991) 254:1024; Hamann et al. Genomics (1996) 32:144). The N-terminal extracellular domain of these receptors contains five conserved cysteines residues involved in disulfide bonds, with a consensus pattern in the region that spans the first three cysteines. One of the most highly conserved regions spans the C-terminal part of the last transmembrane region and the beginning of the adjacent intracellular region and is used as a second signature pattern. The two consensus patterns are: 1) C-x(3)-[FYWLIV]-D-x(3,4)-C-[FW]-x(2)-[STAGV]-x(8,9)-C-[PF]; and 2) Q-G-[LMFCA]-[LIVMFT]-[LIV]-x-[LIVFST]-[LIF]-[VFYH]-C-[LFY]-x-N-x(2)-V

ATPases Associated with Various Cellular Activities (ATPases). Several of the polynucleotides of the invention correspond to a sequence that encodes a member of a family of ATPases Associated with diverse cellular Activities (AAA). The AAA protein family is composed of a large number of ATPases that share a conserved region of about 220 amino acids containing an ATP-binding site (Froehlich et al., J. Cell Biol. (1991) 114:443; Erdmann et al. Cell (1991) 64:499; Peters et al., EMBO J. (1990) 9:1757; Kunau et al., Biochimie (1993) 75:209–224; Confalonieri et al., BioEssays (1995) 17:639; http://yeamob.pci.chemie.uni-tuebingen.de/AAA/Description.html). The AAA domain, which can be present in one or two copies, acts as an ATP-dependent protein clamp (Confalonieri et al. (1995) BioEssays 17:639) and contains a highly conserved region located in the central part of the domain. The consensus pattern is: [LIVMT]-x-[LIVMT]-[LIVMF]-x-[GATMC]-[ST]-[NS]-x(4)-[LIVM]-D-x-A-[LIFA]-x-R.

Basic Region Plus Leucine Zipper Transcription Factors (BZIP). SEQ ID NO:1623 represents a polynucleotide encoding a novel member of the family of basic region plus leucine zipper transcription factors. The bZIP superfamily (Hurst, Protein Prof. (1995) 2:105; and Ellenberger, Curr. Opin. Struct. Biol. (1994) 4:12) of eukaryotic DNA-binding transcription factors encompasses proteins that contain a basic region mediating sequence-specific DNA-binding followed by a leucine zipper required for dimerization. The consensus pattern for this protein family is: [KR]-x(1,3)-[RKSAQ]-N-x(2)-[SAQ](2)-x-[RKTAENQ]-x-R-x-[RK].

C2 domain (C2). SEQ ID NOS: 1715 and 2426 correspond to a sequence encoding a C2 domain, which is involved in calcium-dependent phospholipid binding (Davletov J. Biol. Chem. (1993) 268:26386–26390) or, in proteins that do not bind calcium, the domain may facilitate binding to inositol-1,3,4,5-tetraphosphate (Fukuda et al. J. Biol. Chem. (1994) 269:29206–29211; Sutton et al. Cell (1995) 80:929–938). The consensus sequence is: [ACG]-x(2)-L-x(2,3)-D-x(1,2)-[NGSTLIF]-[GTMR]-x-[STAP]-D-[PA]-[FY].

Cysteine proteases (Cys-protease). SEQ ID NO:2238 represents a polynucleotide encoding a protein having a eukaryotic thiol (cysteine) protease active site. Cysteine proteases (Dufour Biochimie (1988) 70:1335) are a family of proteolytic enzymes that contain an active site cysteine. Catalysis proceeds through a thioester intermediate and is facilitated by a nearby histidine side chain; an asparagine completes the essential catalytic triad. The sequences around the three active site residues are well conserved and can be used as signature patterns: Q-x(3)-[GE]-x-C-[YW]-x(2)-[STAGC]-[STAGCV] (where C is the active site residue); 2) [LIVMGSTAN]-x-H-[GSACE]-[LIVM]-x-[LIVMAT](2)-G-x-[GSADNH] (where H is the active site residue); and 3) [FYCH]-[WI]-[LIVT]-x-[KRQAG]-N-[ST]-W-x(3)-[FYW]-G-x(2)-G-[LFYW]-[LIVMFYG]-x-[LIVMF] (where N is the active site residue).

DEAD and DEAH box families ATP-dependent helicases (Dead box helic). SEQ ID NOS:1630, 1865, and 2517 represent polynucleotides encoding a novel member of the DEAD and DEAH box families (Schmid et al., Mol. Microbiol. (1992) 6:283; Linder et al., Nature (1989) 337:121; Wassarman, et al., Nature (1991) 349:463). All members of these families are involved in ATP-dependent, nucleic-acid unwinding. All DEAD box family members share a number of conserved sequence motifs, some of which are specific to the DEAD family, with others shared by other ATP-binding proteins or by proteins belonging to the helicases ‘superfamily’ (Hodgman Nature (1988) 333:22 and Nature (1988) 333:578 (Errata); http://www.expasy.ch/www/linder/HELICASES_TEXT.html). One of these motifs, called the ‘D-E-A-D-box’, represents a special version of the B motif of ATP-binding proteins. Proteins that have His instead of the second Asp and are ‘D-E-A-H-box’ proteins (Wassarman et al., Nature (1991) 349:463; Harosh, et al., Nucleic Acids Res. (1991) 19:6331; Koonin, et al., J. Gen. Virol. (1992) 73:989; http://www.expasy.ch/www/linder/HELICASES_TEXT.html). The following signature patterns are used to identify member for both subfamilies: 1) [LIVMF](2)-D-E-A-D-[RKEN]-x-[LIVMFYGSTN]; and 2) [GSAH]-x-[LIVMF](3)-D-E-[ALIV]-H-[NECR].

Dual specificity phosphatase (DSPc). Dual specificity phosphatases (DSPs) are Ser/Thr and Tyr protein phosphatases that comprise a tertiary fold highly similar to that of tyrosine-specific phosphatases, except for a “recognition” region connecting helix alpha1 to strand beta1. This tertiary fold may determine differences in substrate specific between VH-1 related dual specificity phosphatase (VHR), the protein tyrosine phosphatases (PTPs), and other DSPs. Phosphatases are important in the control of cell growth, proliferation, differentiation and transformation.

EF Hand (EFhand). SEQ ID NO:1595 corresponds to a polynucleotide encoding a member of the EF-hand protein family, a calcium binding domain shared by many calcium-binding proteins belonging to the same evolutionary family (Kawasaki et al., Protein. Prof. (1995) 2:305–490). The domain is a twelve residue loop flanked on both sides by a twelve residue alpha-helical domain, with a calcium ion coordinated in a pentagonal bipyramidal configuration. The six residues involved in the binding are in positions 1, 3, 5, 7, 9 and 12; these residues are denoted by X, Y, Z, -Y, -X and -Z. The invariant Glu or Asp at position 12 provides two oxygens for liganding Ca (bidentate ligand). The consensus pattern includes the complete EF-hand loop as well as the first residue which follows the loop and which seem to always be hydrophobic: D-x-[DNS]-{ILVFYW}-[DENSTG]-[DNQGHRK]-{GP}-[LIVMC]-[DENQSTAGC]-x(2)-[DE]-[LIVMFYW].

Eukaryotic Aspartyl Proteases (asp). Several of the polynucleotides of the invention correspond to a sequence encoding a novel eukaryotic aspartyl protease. Aspartyl proteases, known as acid proteases, (EC 3.4.23.) are a widely distributed family of proteolytic enzymes (Foltmann., Essays Biochem. (1981) 17:52; Davies, Annu. Rev. Biophys. Chem. (1990) 19:189; Rao, et al., Biochemistry (1991) 30:4663) known to exist in vertebrates, fungi, plants, retroviruses and some plant viruses. Aspartate proteases of eukaryotes are monomeric enzymes which consist of two domains. Each domain contains an active site centered on a catalytic aspartyl residue. The consensus pattern to identify eukaryotic aspartyl protease is: [LIVMFGAC]-[LIVMTADN]-[LIVFSA]-D-[ST]-G-[STAV]-[STAPDENQ]-x-[LIVMFSTNC]-x-[LIVMFGTA], where D is the active site residue.

Fibronectin Type II collagen-binding domain (FntypeII). SEQ ID NO: 1968 corresponds to a polynucleotide encoding a polypeptide having a type II fibronectin collagen binding domain. Fibronectin is a plasma protein that binds cell surfaces and various compounds including collagen, fibrin, heparin, DNA, and actin. The major part of the sequence of fibronectin consists of the repetition of three types of domains, called type I, II, and III (Skorstengaardet al., Eur. J. Biochem. (1986) 161:441). The type II domain, which is duplicated in fibronectin, is approximately forty residues long, contains four conserved cysteines involved in disulfide bonds and is part of the collagen-binding region of fibronectin. The consensus pattern for identifying members of this family, which pattern spans this entire domain, is: C-x(2)-P-F-x-[FYWI]-x(7)-C-x(8,10)-W-C-x(4)-[DNSR]-[FYW]-x(3,5)-[FYW]-x-[FYWI]-C (where the four C's are involved in disulfide bonds).

G-Protein Alpha Subunit (G-alpha). SEQ ID NO: 1779 corresponds to a gene encoding a member of the G-protein alpha subunit family. G-proteins are a family of membrane-associated proteins that couple extracellularly-activated integral-membrane receptors to intracellular effectors, such as ion channels and enzymes that vary the concentration of second messenger molecules. G-proteins are composed of 3 subunits (alpha, beta and gamma) which, in the resting state, associate as a trimer at the inner face of the plasma membrane. The alpha subunit, which binds GTP and exhibits GTPase activity, is about 350–400 amino acids in length with a molecular weight in the range of 40–45 kDa. Seventeen distinct types of alpha subunit have been identified in mammals, and fall into 4 main groups on the basis of both sequence similarity and function: alpha-s, alpha-q, alpha-i and alpha-12 (Simon et al., Science (1993) 252:802). They are often N-terminally acylated, usually with myristate and/or palmitoylate, and these fatty acid modifications can be important for membrane association and high-affinity interactions with other proteins.

Helicases conserved C-terminal domain (helicase C). SEQ ID NOS: 1621 and 1652 represent polynucleotides encoding novel members of the DEAD/H helicase family. The DEAD and DEAH families are described above.

Helix-Loop-Helix (HLH) DNA Binding Domain (HLH). SEQ ID NO:2192 corresponds to a sequence encoding an HLH domain. The HLH domain, which normally spans about 40 to 50 amino acids, is present in a number of eukaryotic transcription factors. The HLH domain is formed of two amphipathic helices joined by a variable length linker region that forms a loop that mediates protein dimerization (Murre et al. Cell (1989) 56:777–783). Basic HLH proteins (bHLH), which have an extra basic region of about 15 amino acid residues adjacent the HLH domain and specifically bind to DNA, include two groups: class A (ubiquitous) and class B (tissue-specific). bHLH family members bind variations of the E-box motif (CANNTG). The homo- or heterodimerization mediated by the HLH domain is independent of, but necessary for DNA binding, as two basic regions are required for DNA binding activity. The HLH proteins lacking the basic domain function as negative regulators since they form heterodimers, but fail to bind DNA. Consensus pattern: [DENSTAP]-[KTR]-[LIVMAGSNT]-{FYWCPHKR}-[LIVMT]-[LIVM]-x(2)-[STAV]-[LIVMSTACKR]-x-[VMFYH]-[LIVMTA]-{P}-{P}-[LIVMRKHQ].

Kinase Domain of Tors. The TOR profile is directed towards a lipid kinase protein family. This family is composed of large proteins with a lipid and protein kinase domain and characterized through their sensitivity to rapamycin (an antifungal compound). TOR proteins are involved in signal transduction downstream of P13 kinase and many other signals. TOR (also called FRAP, RAFT) plays a role in regulating protein synthesis and cell growth., and in yeast controls translation initiation and early G1 progression. See, e.g., Barbet et al. Mol Biol Cell. (1996) 7(1):25–42; Helliwell et al. Genetics (1998) 148:99–112.

MAP kinase kinase (mkk). SEQ ID NOS: 1825,1876, 2039, and 2526 represent members of the MAP kinase kinase (mkk) family. MAP kinases (MAPK) are involved in signal transduction, and are important in cell cycle and cell growth controls. The MAP kinase kinases (MAPKK) are dual-specificity protein kinases which phosphorylate and activate MAP kinases. MAPKK homologues have been found in yeast, invertebrates, amphibians, and mammals. Moreover, the MAPKK/MAPK phosphorylation switch constitutes a basic module activated in distinct pathways in yeast and in vertebrates. MAPKKs are essential transducers through which signals must pass before reaching the nucleus. For review, see, e.g., Biologique Biol Cell (1993) 79:193–207; Nishida et al., Trends Biochem Sci (1993) 18:128–31; Ruderman Curr Opin Cell Biol (1993) 5:207–13; Dhanasekaran et al., Oncogene (1998) 17:1447–55; Kiefer et al., Biochem Soc Trans (1997) 25:491–8; and Hill, Cell Signal (1996) 8:533–44.

Neurotransmitter-Gated Ion-Channel (neur_chan). Several of the sequences correspond to a sequence encoding a neurotransmitter-gated ion channel. Neurotransmitter-gated ion-channels, which provide the molecular basis for rapid signal transmission at chemical synapses, are post-synaptic oligomeric transmembrane complexes that transiently form a ionic channel upon the binding of a specific neurotransmitter. Five types of neurotransmitter-gated receptors are known: 1) nicotinic acetylcholine receptor (AchR); 2) glycine receptor; 3) gamma-aminobutyric-acid (GABA) receptor; 4) serotonin 5HT3 receptor; and 5) glutamate receptor. All known sequences of subunits from neurotransmitter-gated ion-channels are structurally related, and are composed of a large extracellular glycosylated N-terminal ligand-binding domain, followed by three hydrophobic transmembrane regions that form the ionic channel, followed by an intracellular region of variable length. A fourth hydrophobic region is found at the C-terminal of the sequence. The consensus pattern is: C-x-[LIVMFQ]-x-[LIVMF]-x(2)-[FY]-P-x-D-x(3)-C, where the two C's are linked by a disulfide bond.

Protein Kinase (protkinase). Several sequences represent polynucleotides encoding protein kinases, which catalyze phosphorylation of proteins in a variety of pathways, and are implicated in cancer. Eukaryotic protein kinases (Hanks, et al., FASEB J. (1995) 9:576; Hunter, Meth. Enzymol. (1991) 200:3; Hanks, et al., Meth. Enzymol. (1991) 200:38; Hanks, Curr. Opin. Struct. Biol. (1991) 1:369; Hanks et al., Science (1988) 241:42) belong to a very extensive family of proteins that share a conserved catalytic core common to both serine/threonine and tyrosine protein kinases. There are a number of conserved regions in the catalytic domain of protein kinases. The first region, located in the N-terminal extremity of the catalytic domain, is a glycine-rich stretch of residues in the vicinity of a lysine residue, which has been shown to be involved in ATP binding. The second region, located in the central part of the catalytic domain, contains a conserved an aspartic acid residue that is important for the catalytic activity of the enzyme (Knighton, et al., Science (1991) 253:407).

The protein kinase profile includes two signature patterns for this second region: one specific for serine/threonine kinases and the other for tyrosine kinases. A third profile is based on the alignment in (Hanks, et al., FASEB J. (1995) 9:576) and covers the entire catalytic domain. The consensus patterns are as follows: 1) [LIV]-G-{P}-G-{P}-[FYWMGSTNH]-[SGA]-{PW}-[LIVCAT]-{PD}-x-[GSTACLIVMFY]-x(5,18)-[LIVMFYWCSTAR]-[AIVP]-[LIVMFAGCKR]-K, where K binds ATP; 2) [LIVMFYC]-x-[HY]-x-D-[LIVMFY]-K-x(2)-N-[LIVMFYCT](3), where D is an active site residue; and 3) [LIVMFYC]-x-[HY]-x-D-[LIVMFY]-[RSTAC]-x(2)-N-[LIVMFYC], where D is an active site residue.

Protein Tyrosine Phosphatase (Y phosphatase) (PTPase). SEQ ID NOS:1719, 1769, 2062, 2197, and 2275 represent polynucleotides encoding a tyrosine-specific protein phosphatase, a kinase that catalyzes the removal of a phosphate groups attached to a tyrosine residue (EC 3.1.3.48) (PTPase) (Fischer et al., Science (1991) 253:401; Charbonneau et al., Annu. Rev. Cell Biol. (1992) 8:463; Trowbridge Biol. Chem. (1991) 266:23517; Tonks et al., Trends Biochem. Sci. (1989) 14:497; and Hunter, Cell (1989) 58:1013). PTPases are important in the control of cell growth, proliferation, differentiation and transformation. Multiple forms of PTPase have been characterized and can be classified into two categories: soluble PTPases and transmembrane receptor proteins that contain PTPase domain(s). Structurally, all known receptor PTPases are made up of a variable length extracellular domain, followed by a transmembrane region and a C-terminal catalytic cytoplasmic domain. PTPase domains consist of about 300 amino acids. Two conserved cysteines are absolutely required for activity, with a number of other conserved residues in the immediate vicinity also important for activity. The consensus pattern for PTPases is: [LIVMF]-H-C-x(2)-G-x(3)-[STC]-[STAGP]-x-[LIVMFY]; C is the active site residue.

RNA Recognition Motif (rrm). SEQ ID NOS: 1850 and 2194 correspond to sequence encoding an RNA recognition motif, also known as an RRM, RBD, or RNP domain. This domain, which is about 90 amino acids long, is contained in eukaryotic proteins that bind single-stranded RNA (Bandziulis et al. Genes Dev. (1989) 3:431–437; Dreyfuss et al. Trends Biochem. Sci. (1988) 13:86–91). Two regions within the RNA-binding domain are highly conserved: the first is a hydrophobic segment of six residues (which is called the RNP-2 motif), the second is an octapeptide motif (which is called RNP-1 or RNP-CS). The consensus pattern is: [RK]-G-{EDRKHPCG}-[AGSCI]-[FY]-[LIVA]-x-[FYLM].

SH2 Domain (SH2). SEQ ID NO: 2441 corresponds to a sequence encoding an SH2 domain. The Src homology 2 (SH2) domain includes an approximately 100 amino acid residue domain, which is conserved in the oncoproteins Src and Fps, as well as in many other intracellular signal-transducing proteins (Sadowski et al. Mol Cell. Biol. (1986) 6:4396–4408; Russel et al. FEBS Lett. (1992) 304:15–20). SH2 domains function as regulatory modules of intracellular signaling cascades by interacting with high affinity to phosphotyrosine-containing target peptides in a sequence-specific and strictly phosphorylation-dependent manner. The SH2 domain has a conserved 3D structure consisting of two alpha helices and six to seven beta-strands. The core of the domain is formed by a continuous beta-meander composed of two connected beta-sheets (Kuriyan et al. Curr. Opin. Struct. Biol. (1993) 3:828–837).

Thioredoxin family active site (Thioredox). SEQ ID NO: 1618 represents a polynucleotide encoding a protein of the thioredoxin family. Thioredoxins are small proteins of approximately one hundred amino acid residues that participate in various redox reactions via the reversible oxidation of an active center disulfide bond (Holmgren, Annu. Rev. Biochem. (1985) 54:237; Gleason, et al., FEMS Microbiol. Rev. (1988) 54:271; Holmgren A. J. Biol. Chem. (1989) 264:13963; Eklund, et al. Proteins (1991) 11:13). Thioredoxins exist in either reduced or oxidized forms where the two cysteine residues are linked in an intramolecular disulfide bond. The sequence around the redox-active disulfide bond is well conserved. The consensus pattern is: [LIVMF]-[LIVMSTA]-x-[LIVMFYC]-[FYWSTHE]-x(2)-[FYWGTN]-C-[GATPLVE]-[PHYWSTA]-C-x(6)-[LIVMFYWT] (where the two C's form the redox-active bond).

Trypsin (trypsin). SEQ ID NOS: 1579, 2290, 2341, 2421, 2430, and 2438 correspond to novel serine proteases of the trypsin family. The catalytic activity of the serine proteases from the trypsin family is provided by a charge relay system involving an aspartic acid residue hydrogen-bonded to a histidine, which itself is hydrogen-bonded to a serine. The sequences in the vicinity of the active site serine and histidine residues are well conserved (Brenner Nature (1988) 334:528). The consensus patterns for the trypsin protein family are: 1) [LIVM]-[ST]-A-[STAG]-H-C, where H is the active site residue; and 2) [DNSTAGC]-[GSTAPIMVQH]-x(2)-G-[DE]-S-G-[GS]-[SAP]-[LIVMFYWH]-[LIVMFYSTANQH], where S is the active site residue. All sequences known to belong to this family are detected by the above consensus sequences, except for 18 different proteases which have lost the first conserved glycine. If a protein includes both the serine and the histidine active site signatures, the probability of it being a trypsin family serine protease is 100%.

WD Domain, G-Beta Repeats (WD domain). SEQ ID NO: 2281 represents a members of the WD domain/G-beta repeat family. Beta-transducin (G-beta) is one of the three subunits (alpha, beta, and gamma) of the guanine nucleotide-binding proteins (G proteins) which act as intermediaries in the transduction of signals generated by transmembrane receptors (Gilman, Annu. Rev. Biochem. (1987) 56:615). The alpha subunit binds to and hydrolyzes GTP; the beta and gamma subunits are required for the replacement of GDP by GTP as well as for membrane anchoring and receptor recognition. In higher eukaryotes, G-beta exists as a small multigene family of highly conserved proteins of about 340 amino acid residues. Structurally, G-beta has eight tandem repeats of about 40 residues, each containing a central Trp-Asp motif (this type of repeat is sometimes called a WD-40 repeat). The consensus pattern for the WD domain/G-Beta repeat family is: [LIVMSTAC]-[LIVMFYWSTAGC]-[LIMSTAG]-[LIVMSTAGC]-x(2)-[DN]-x(2)-[LIVMWSTAC]-x-[LIVMFSTAG]-W-[DEN]-[LIVMFSTAGCN].

wnt Family of Developmental Signaling Proteins (Wnt dev sign). Several of the sequences correspond to novel members of the wnt family of developmental signaling proteins. Wnt-1 (previously known as int-1), the seminal member of this family, (Nusse, Trends Genet. (1988) 4:291) plays a role in intercellular communication and is important in central nervous system development. All wnt family proteins share the following features characteristic of secretory proteins: a signal peptide, several potential N-glycosylation sites and 22 conserved cysteines that may be involved in disulfide bonds. Wnt proteins generally adhere to the plasma membrane of secreting cells and are therefore likely to signal over only few cell diameters. The consensus pattern, which is based upon a highly conserved region including three cysteines, is as follows: C-K-C-H-G-[LIVMT]-S-G-x-C.

Zinc Finger, C₂H₂ Type (Zincfing C₂H₂). SEQ ID NOS: 1735, 1942, 2018, 2254, and 2515 correspond to polynucleotides encoding members of the C₂H₂ type zinc finger protein family, which contain zinc finger domains that facilitate nucleic acid binding (Klug et al., Trends Biochem. Sci. (1987) 12:464; Evans et al., Cell (1988) 52:1; Payre et al., FEBS Lett. (1988) 234:245; Miller et al., EMBO J. (1985) 4:1609; and Berg, Proc. Natl. Acad. Sci. USA (1988) 85:99). In addition to the conserved zinc ligand residues, a number of other positions are also important for the structural integrity of the C₂H₂ zinc fingers. (Rosenfeld et al., J. Biomol. Struct. Dyn. (1993) 11:557) The best conserved position, which is generally an aromatic or aliphatic residue, is located four residues after the second cysteine. The consensus pattern for C₂H₂ zinc fingers is: C-x(2,4)-C-x(3)-[LIVMFYWC]-x(8)-H-x(3,5)-H. The two C's and two H's are zinc ligands.

Example 4 Differential Expression of Polynucleotides of the Invention: Description of Libraries and Detection of Differential Expression

The relative expression levels of the polynucleotides of the invention was assessed in several libraries prepared from various sources, including cell lines and patient tissue samples. Table 4 provides a summary of these libraries, including the shortened library name (used hereafter), the mRNA source used to prepared the cDNA library, the “nickname” of the library that is used in the tables below (in quotes), and the approximate number of clones in the library.

TABLE 4 Description of cDNA Libraries Number of Library Clones in (lib #) Description Cluster 1 Km12L4 307133 Human Colon Cell Line, High Metastatic Potential (derived from Km12C); “High Met Colon” 2 Km12C 284755 Human Colon Cell Line, Low Metastatic Potential; “Low Met Colon” 3 MDA-MB-231 326937 Human Breast Cancer Cell Line, High Metastatic Potential; micrometastases in lung; “High Met Breast” 4 MCF7 318979 Human Breast Cancer Cell, Non Metastatic; “Low Met Breast” 8 MV-522 223620 Human Lung Cancer Cell Line, High Metastatic Potential; “High Met Lung” 9 UCP-3 312503 Human Lung Cancer Cell Line, Low Metastatic Potential; “Low Met Lung” 12 Human microvascular endothelial cells (HMEC) - 41938 Untreated PCR (OligodT) cDNA library; “HMEC” 13 Human microvascular endothelial cells (HMEC) - 42100 Basic fibroblast growth factor (bFGF) treated PCR (OligodT) cDNA library; “HMEC-bFGF” 14 Human microvascular endothelial cells (HMEC) - 42825 Vascular endothelial growth factor (VEGF) treated PCR (OligodT) cDNA library; “HMEC-VEGF” 15 Normal Colon - UC#2 Patient 282722 PCR (OligodT) cDNA library; “Normal Colon Tissue” 16 Colon Tumor - UC#2 Patient 298831 PCR (OligodT) cDNA library; “Normal Colon Tumor Tissue” 17 Liver Metastasis from Colon Tumor of 303467 UC#2 Patient PCR (OligodT) cDNA library; “High Met Colon Tissue” 18 Normal Colon - UC#3 Patient 36216 PCR (OligodT) cDNA library; “Normal Colon Tissue” 19 Colon Tumor - UC#3 Patient 41388 PCR (OligodT) cDNA library; “Colon Tumor Tissue” 20 Liver Metastasis from Colon Tumor of 30956 UC#3 Patient PCR (OligodT) cDNA library; “High Met Colon Tissue” 21 GRRpz 164801 Human Prostate Cell Line; “Normal Prostate” 22 Woca 162088 Human Prostate Cancer Cell Line; “Prostate Cancer”

The KM12L4, KM12C, and MDA-MB-231 cell lines are described in Example 1 above. The MCF7 cell line was derived from a pleural effusion of a breast adenocarcinoma and is non-metastatic. The MV-522 cell line is derived from a human lung carcinoma and is of high metastatic potential. The UCP-3 cell line is a low metastatic human lung carcinoma cell line; the MV-522 is a high metastatic variant of UCP-3. These cell lines are well-recognized in the art as models for the study of human breast and lung cancer (see, e.g., Chandrasekaran et al., Cancer Res. (1979) 39:870 (MDA-MB-231 and MCF-7); Gastpar et al., J Med Chem (1998) 41:4965 (MDA-MB-231 and MCF-7); Ranson et al., Br J Cancer (1998) 77:1586 (MDA-MB-231 and MCF-7); Kuang et al., Nucleic Acids Res (1998)26:1116 (MDA-MB-231 and MCF-7); Varki et al., Int J Cancer (1987) 40:46 (UCP-3); Varki et al., Tumour Biol. (1990) 11:327; (MV-522 and UCP-3); Varki et al., Anticancer Res. (1990) 10:637; (MV-522); Kelner et al., Anticancer Res (1995) 15:867 (MV-522); and Zhang et al., Anticancer Drugs (1997) 8:696 (MV522)). The samples of libraries 15–20 are derived from two different patients (UC#2, and UC#3). The bFGF-treated HMEC were prepared by incubation with bFGF at 10 ng/ml for 2 hrs; the VEGF-treated HMEC were prepared by incubation with 20 ng/ml VEGF for 2 hrs. Following incubation with the respective growth factor, the cells were washed and lysis buffer added for RNA preparation. The GRRpz and WOca cell lines were provided by Dr. Donna M. Peehl, Department of Medicine, Stanford University School of Medicine. GRRpz was derived from normal prostate epithelium. The WOca cell line is a Gleason Grade 4 cell line.

Each of the libraries is composed of a collection of cDNA clones that in turn are representative of the mRNAs expressed in the indicated mRNA source. In order to facilitate the analysis of the millions of sequences in each library, the sequences were assigned to clusters. The concept of “cluster of clones” is derived from a sorting/grouping of cDNA clones based on their hybridization pattern to a panel of roughly 300 7 bp oligonucleotide probes (see Drmanac et al., Genomics (1996) 37(1):29). Random cDNA clones from a tissue library are hybridized at moderate stringency to 300 7 bp oligonucleotides. Each oligonucleotide has some measure of specific hybridization to that specific clone. The combination of 300 of these measures of hybridization for 300 probes equals the “hybridization signature” for a specific clone. Clones with similar sequence will have similar hybridization signatures. By developing a sorting/grouping algorithm to analyze these signatures, groups of clones in a library can be identified and brought together computationally. These groups of clones are termed “clusters”. Depending on the stringency of the selection in the algorithm (similar to the stringency of hybridization in a classic library cDNA screening protocol), the “purity” of each cluster can be controlled. For example, artifacts of clustering may occur in computational clustering just as artifacts can occur in “wet-lab” screening of a cDNA library with 400 bp cDNA fragments, at even the highest stringency. The stringency used in the implementation of cluster herein provides groups of clones that are in general from the same cDNA or closely related cDNAs. Closely related clones can be a result of different length clones of the same cDNA, closely related clones from highly related gene families, or splice variants of the same cDNA.

Differential expression for a selected cluster was assessed by first determining the number of cDNA clones corresponding to the selected cluster in the first library (Clones in 1^(st)), and the determining the number of cDNA clones corresponding to the selected cluster in the second library (Clones in 2^(nd)). Differential expression of the selected cluster in the first library relative to the second library is expressed as a “ratio” of percent expression between the two libraries. In general, the “ratio” is calculated by: 1) calculating the percent expression of the selected cluster in the first library by dividing the number of clones corresponding to a selected cluster in the first library by the total number of clones analyzed from the first library; 2) calculating the percent expression of the selected cluster in the second library by dividing the number of clones corresponding to a selected cluster in a second library by the total number of clones analyzed from the second library; 3) dividing the calculated percent expression from the first library by the calculated percent expression from the second library. If the “number of clones” corresponding to a selected cluster in a library is zero, the value is set at 1 to aid in calculation. The formula used in calculating the ratio takes into account the “depth” of each of the libraries being compared, i.e., the total number of clones analyzed in each library.

In general, a polynucleotide is said to be significantly differentially expressed between two samples when the ratio value is greater than at least about 2, preferably greater than at least about 3, more preferably greater than at least about 5, where the ratio value is calculated using the method described above. The significance of differential expression is determined using a z score test (Zar, Biostatistical Analysis, Prentice Hall, Inc., USA, “Differences between Proportions,” pp 296–298 (1974).

Examples 5–12 Differential Expression of Polynucleotides of the Invention

A number of polynucleotide sequences have been identified that are differentially expressed between, for example, cells derived from high metastatic potential cancer tissue and low metastatic cancer cells, and between cells derived from high metastatic potential cancer tissue and normal tissue. Evaluation of the levels of expression of the genes corresponding to these sequences can be valuable in diagnosis, prognosis, and/or treatment (e.g., to facilitate rationale design of therapy, monitoring during and after therapy, etc.). Moreover, the genes corresponding to differentially expressed sequences described herein can be therapeutic targets due to their involvement in regulation (e.g., inhibition or promotion) of development of, for example, the metastatic phenotype. For example, sequences that correspond to genes that are increased in expression in high metastatic potential cells relative to normal or non-metastatic tumor cells may encode genes or regulatory sequences involved in processes such as angiogenesis, differentiation, cell replication, and metastasis.

Detection of the relative expression levels of differentially expressed polynucleotides described herein can provide valuable information to guide the clinician in the choice of therapy. For example, a patient sample exhibiting an expression level of one or more of these polynucleotides that corresponds to a gene that is increased in expression in metastatic or high metastatic potential cells may warrant more aggressive treatment for the patient. In contrast, detection of expression levels of a polynucleotide sequence that corresponds to expression levels associated with that of low metastatic potential cells may warrant a more positive prognosis than the gross pathology would suggest.

A number of polynucleotide sequences of the present invention are differentially expressed between human microvascular endothelial cells (HMEC) that have been treated with growth factors relative to untreated HMEC. Sequences that are differentially expressed between growth factor-treated HMEC and untreated HMEC can represent sequences encoding gene products involved in angiogenesis, metastasis (cell migration), and other development and oncogenic processes. For example, sequences that are more highly expressed in HMEC treated with growth factors (such as bFGF or VEGF) relative to untreated HMEC can serve as markers of cancer cells of higher metastatic potential. Detection of expression of these sequences in colon cancer tissue can be valuable in determining diagnostic, prognostic and/or treatment information associated with the prevention of achieving the malignant state in these tissues, and can be important in risk assessment for a patient. A patient sample displaying an increased level of one or more of these polynucleotides may thus warrant closer attention or more frequent screening procedures to catch the malignant state as early as possible.

The differential expression of the polynucleotides described herein can thus be used as, for example, diagnostic markers, prognostic markers, for risk assessment, patient treatment and the like. These polynucleotide sequences can also be used in combination with other known molecular and/or biochemical markers. The following examples provide relative expression levels of polynucleotides from specified cell lines and patient tissue samples.

Example 5 High Metastatic Potential Breast Cancer Versus Low Metastatic Breast Cancer Cells

The following tables summarize polynucleotides that represent genes that are differentially expressed between high metastatic potential and low metastatic potential breast cancer cells.

TABLE 5 High metastatic potential breast (lib3) > low metastatic potential (lib4) breast cancer cells SEQ ID NO: Lib3 Clones Lib4 Clones Lib3/Lib4 1213 40 0 39 1538 60 3 20 1466 14 0 14 1356 10 0 10 1383 10 1 10 1158 10 1 10 441 10 1 10 1338 10 0 10 1426 19 2 9 1547 9 1 9 1313 8 1 8 841 8 1 8 1534 8 0 8 1503 8 0 8 829 8 1 8 1408 8 0 8 1447 7 0 7 1389 7 0 7 356 7 0 7 1492 7 0 7 1543 22 3 7 799 7 0 7 1437 6 0 6 1251 6 0 6 972 18 3 6 1482 6 0 6 1299 6 0 6 109 24 4 6 1558 6 0 6 1355 6 0 6 1548 11 2 5 250 10 2 5 919 26 6 4 358 36 12 3 1525 75 28 3 1157 49 17 3

TABLE 6 Low metastatic potential breast (lib4) > high metastatic potential breast cancer cells (lib3) SEQ ID NO: Lib3 Clones Lib4 Clones Lib4/Lib3 248 0 58 59 726 1 23 24 14 1 19 19 699 0 14 14 763 1 14 14 20 1 13 13 79 1 13 13 715 0 10 10 991 0 8 8 1199 0 8 8 707 0 7 7 1128 4 26 7 891 0 6 6 1146 2 11 6 731 7 44 6 1518 3 15 5 340 3 13 4 949 4 13 3 1247 7 18 3 1185 497 1216 3

Example 6 High Metastatic Potential Lung Cancer Versus Low Metastatic Lung Cancer Cells

The following summarizes polynucleotides that represent genes differentially expressed between high metastatic potential lung cancer cells and low metastatic potential lung cancer cells:

TABLE 7 High metastatic potential lung (lib8) > low metastatic potential lung (lib9) lung cancer cells SEQ ID NO: Lib8 Clones Lib9 Clones Lib8/Lib9 150 31 0 43 651 43 2 30 1298 14 1 20 57 11 0 15 625 7 0 10 1322 7 1 10 36 7 0 10 621 18 3 8 215 6 1 8 561 19 4 7 247 5 0 7 199 5 0 7 998 5 0 7 502 5 0 7 1382 8 2 6 1181 17 4 6 1309 8 2 6 1157 15 4 5 1260 14 5 4 1185 710 266 4 1525 21 10 3

TABLE 8 Low metastatic potential lung (lib9) > high metastatic potential lung (lib8) cancer cells SEQ ID NO: Lib8 Clones Lib9 Clones Lib9/Lib8 924 1 13 9 822 1 13 9 728 1 12 9 341 1 12 9 1527 3 31 7 698 4 26 5 949 2 15 5 744 3 23 5 973 8 27 2

Example 7 High Metastatic Potential Colon Cancer Versus Low Metastatic Colon Cancer Cells

Tables 9 and 10 summarize polynucleotides that represent genes differentially expressed between high metastatic potential and low metastatic potential colon cancer cells:

TABLE 9 High metastatic potential (lib1) > low metastatic potential (lib2) colon cancer cells SEQ ID NO: Lib1 Clones Lib2 Clones Lib1/Lib2 248 67 2 31 87 12 0 11 698 11 0 10 57 13 3 4 924 24 10 2 1249 24 9 2

TABLE 10 Low metastatic potential (lib2) > high metastatic potential colon cancer (lib1) cells SEQ ID NO: Lib1 Clones Lib2 Clones Lib2/Lib1 1268 1 17 18 1114 0 15 16 1032 1 14 15 109 5 60 13 973 1 11 12 91 1 11 12 982 0 9 10 1267 3 28 10 93 1 8 9 1556 1 8 9 1251 0 8 9 1206 2 17 9 812 0 8 9 1254 0 7 8 1220 0 7 8 766 0 7 8 1156 0 7 8 1007 0 7 8 981 0 7 8 762 0 7 8 876 0 6 6 1234 2 11 6 1183 0 6 6 1044 2 12 6 785 0 6 6 1069 3 17 6 770 0 6 6 778 0 6 6 792 0 6 6 822 2 10 5 1258 7 23 4 1224 7 17 3 984 8 19 3 841 10 28 3 339 14 34 3 1213 11 29 3 1201 5 14 3 1192 22 48 2

Example 8 High Metastatic Potential Colon Cancer Patient Tissue Vs. Normal Patient Tissue

Tables 11 summarizes polynucleotides that represent genes differentially expressed between high metastatic potential colon cancer cells and normal colon cells of patient tissue.

TABLE 11 High metastatic potential colon tissue (lib17) vs. normal colon tissue (lib 15) SEQ ID NO: Lib15 Clones Lib17 Clones Lib17/Lib15 1422 1 13 12  1132 1 10 9 730 1 9 8 1311 0 7 7 78 9 48 5 822 5 20 4 Lib15/Lib17 463 8 1 9

Example 9 High Tumor Potential Colon Tissue Vs. Metastasized Colon Cancer Tissue

The following table summarizes polynucleotides that represent genes differentially expressed between high tumor potential colon cancer cels and cells derived from high metastatic potential colon cancer cells of a patient.

TABLE 12 High tumor potential colon tissue (lib16) vs. high metastatic colon tissue (lib 17) SEQ ID NO: Lib16 Clones Lib17 Clones Lib16/Lib17 1185 14 4  4 Lib17/Lib16 822 2 20 10

Example 10 High Tumor Potential Colon Cancer Patient Tissue Versus Normal Patient Tissue

Tables 13 and 14 summarize polynucleotides that represent genes differentially expressed between high metastatic potential colon cancer cells and normal colon cells in patient tissue:

TABLE 13 Higher expression in tumor potential colon tissue (lib16) vs. normal colon tissue (lib15) SEQ ID NO: Lib15 Clones Lib16 Clones Lib16/Lib15 1311 0 8 8 78 9 28 3

TABLE 14 Higher expression in normal colon tissue (lib15) vs. tumor potential colon tissue (lib16) SEQ ID NO: Lib15 Clones Lib16 Clones Lib15/Lib16 463 8 0 8 1099 12 3 4

Example 11 Growth Factor-Stimulated Human Microvascular Endothelial Cells (HMEC) Relative to Untreated HMEC

The following tables summarize polynucleotides that represent genes differentially expressed between growth factor-treated and untreated HMEC.

TABLE 15 Higher expression in bFGF treated HMEC (lib13) vs. untreated HMEC (lib12) SEQ ID NO: Lib12 Clones Lib13 Clones Lib13/Lib12 1520 9 23 3 1538 17 35 2

TABLE 16 Higher expression in VEGF treated HMEC (lib14) vs. untreated HMEC (lib12) SEQ ID NO: Lib12 Clones Lib14 Clones Lib14/Lib12 1154 2 12 6 1226 2 10 5 1538 17 38 2

Example 12 Polynucleotides Differentially Expressed in Human Prostate Cancer Cells Relative to Normal Human Prostate Cells

The following tables summarize identified polynucleotides that represent genes differentially expressed between prostate cancer cells and normal prostate cells:

TABLE 17 Higher expression in normal prostate cells (lib21) relative to prostate cancer cells (lib22) SEQ ID NO: Lib21 Clones Lib22 Clones Lib21/Lib22 1525 6 0 6 248 116 51 2 1203 22 9 2

TABLE 18 Higher expression in prostate cancer cells (lib22) relative to normal prostate cells (lib21) SEQ ID NO: Lib21 Clones Lib22 Clones Lib22/Lib21 1213 0 34 35 340 1 12 12 699 0 11 11

Example 13 Differential Expression Across Multiple Libraries

A number of polynucleotide sequences have been identified that represent genes that are differentially expressed across multiple libraries. Expression of these sequences in a tissue or any origin can be valuable in determining diagnostic, prognostic and/or treatment information associated with the prevention of achieving the malignant state in these tissues, and can be important in risk assessment for a patient. These polynucleotides can also serve as non-tissue specific markers of, for example, risk of metastasis of a tumor. Table 19 summarizes this data.

TABLE 19 Genes Differentially Expressed Across Multiple Library Comparisons SEQ ID NO: Cell or Tissue Sample and Cancer State Compared Ratio 57 High Met Lung (lib8) > Low Met Lung (lib9) 15 57 High Met Colon (lib1) > Low Met Colon (lib2) 4 78 High Met Colon Tissue (lib17) > Normal Colon 5 Tissue (lib15) 78 Normal Colon Tumor Tissue (lib16) > 3 Normal Colon Tissue (lib15) 109 High Met Breast (lib3) > Low Met Breast (lib4) 6 109 Low Met Colon (lib2) > High Met Colon (lib1) 13 248 High Met Colon (lib1) > Low Met Colon (lib2) 31 248 Normal Prostate (lib21) > Prostate Cancer (lib22) 2 248 Low Met Breast (lib4) > High Met Breast (lib3) 59 340 Prostate Cancer (lib22) > Normal Prostate (lib21) 12 340 Low Met Breast (lib4) > High Met Breast (lib3) 4 463 Normal Colon Tissue (lib15) > High Met Colon 9 Tissue (lib17) 463 Normal Colon Tissue (lib15) > Normal Colon 8 Tumor Tissue (lib16) 698 High Met Colon (lib1) > Low Met Colon (lib2) 10 698 Low Met Lung (lib9) > High Met Lung (lib8) 5 699 Low Met Breast (lib4) > High Met Breast (lib3) 14 699 Prostate Cancer (lib22) > Normal Prostate (lib21) 11 822 High Met Colon Tissue (lib17) > Normal Colon 10 Tumor Tissue (lib16) 822 Low Met Lung (lib9) > High Met Lung (lib8) 9 822 Low Met Colon (lib2) > High Met Colon (lib1) 5 822 High Met Colon Tissue (lib17) > Normal 4 Colon Tissue (lib15) 841 High Met Breast (lib3) > Low Met Breast (lib4) 8 841 Low Met Colon (lib2) > High Met Colon (lib1) 3 924 High Met Colon (lib1) > Low Met Colon (lib2) 2 924 Low Met Lung (lib9) > High Met Lung (lib8) 9 949 Low Met Lung (lib9) > High Met Lung (lib8) 5 949 Low Met Breast (lib4) > High Met Breast (lib3) 3 973 Low Met Colon (lib2) > High Met Colon (lib1) 12 973 Low Met Lung (lib9) > High Met Lung (lib8) 2 1157 High Met Lung (lib8) > Low Met Lung (lib9) 5 1157 High Met Breast (lib3) > Low Met Breast (lib4) 3 1185 Normal Colon Tumor Tissue (lib16) > High Met 4 Colon Tissue (lib17) 1185 High Met Lung (lib8) > Low Met Lung (lib9) 4 1185 Low Met Breast (lib4) > High Met Breast (lib3) 3 1213 High Met Breast (lib3) > Low Met Breast (lib4) 39 1213 Prostate Cancer (lib22) > Normal Prostate (lib21) 35 1213 Low Met Colon (lib2) > High Met Colon (lib1) 3 1251 High Met Breast (lib3) > Low Met Breast (lib4) 6 1251 Low Met Colon (lib2) > High Met Colon (lib1) 9 1311 Normal Colon Tumor Tissue (lib16) > Normal 8 Colon Tissue (lib15) 1311 High Met Colon Tissue (lib17) > Normal 7 Colon Tissue (lib15) 1525 Normal Prostate (lib21) > Prostate Cancer (lib22) 6 1525 High Met Lung (lib8) > Low Met Lung (lib9) 3 1525 High Met Breast (lib3) > Low Met Breast (lib4) 3 1538 High Met Breast (lib3) > Low Met Breast (lib4) 20 1538 HMEC-VEGF (lib14) > HMEC (lib12) 2 1538 HMEC-bFGF (lib13) > HMEC (lib12) 2 Key for Table 19: High Met = high metastatic potential; Low Met = low metastatic potential; met = metastasized; tumor = non-metastasized tumor; HMEC = human microvascular endothelial cell; bFGF = bFGF treated; VEGF = VEGF treated.

Example 14 Identification of Contiguous Sequences Having a Polynucleotide of the Invention

The novel polynucleotides were used to screen publicly available and proprietary databases to determine if any of the polynucleotides of SEQ ID NOS:2611–2707 would facilitate identification of a contiguous sequence, e.g., the polynucleotides would provide sequence that would result in 5′ extension of another DNA sequence, resulting in production of a longer contiguous sequence composed of the provided polynucleotide and the other DNA sequence(s). Contiging was performed using the Gelmerge application (default settings) of GCG from the Univ. of Wisconsin.

Using these parameters, 97 contiged sequences were generated. These contiged sequences are provided as SEQ ID NOS:2611–2707 (see Table 1C). Table 1C provides the SEQ ID NO of the contig sequence, the name of the sequence used to create the contig, and the accession number of the publicly available tentative human consensus (THC) sequence used with the sequence of the corresponding sequence name to provide the contig. The sequence name of Table 1C can be correlated with the SEQ ID NO: of the polynucleotide of the invention using Tables 1A and 1B.

The contiged sequences (SEQ ID NOS:2611–2707) thus represent longer sequences that encompass a polynucleotide sequence of the invention. The contiged sequences were then translated in all three reading frames to determine the best alignment with individual sequences using the BLAST programs as described above. The sequences were masked using the XBLAST program for masking low complexity as described above in Example 1. Several of the contiged sequences were found to encode polypeptides having characteristics of a polypeptide belonging to a known protein families (and thus represent new members of these protein families) and/or comprising a known functional domain (Table 3B, inserted prior to claims). Thus the invention encompasses fragments, fusions, and variants of such polynucleotides that retain biological activity associated with the protein family and/or functional domain identified herein.

Descriptions of the profiles for the indicated protein families and functional domains are provided in Example 3 above. A description of the profile for PR55 is provided below.

Protein Phosphatase 2A Regulatory Subunit PR55 (PR55). Several of the contigs correspond to a sequence encoding a protein comprising a protein phosphatase 2A (PP2A) regulatory subunit PR55. PP2A is a serine/threonine phosphatase involved in many aspects of cellular function including the regulation of metabolic enzymes and proteins involved in signal transduction. PP2A is a trimeric enzyme comprising a core composed of a catalytic subunit associated with a 65 Kd regulatory subunit (PR65, also called subunit A). This complex associates with a third variable subunit (subunit B), which confers distinct properties to the holoenzyme (Mayer-Jaekel et al. Trends Cell Biol. (1994) 4:287–291). One of the forms of the variable subunit is a 55 Kd protein (PR55) which is highly conserved in mammals and may facilitate substrate recognition or targeting the enzyme complex to the appropriate subcellular compartment. The PR55 subunit comprises two conserved sequences of 15 residues; one located in the N-terminal region, the other in the center of the protein. The consensus patterns are: E-F-D-Y-L-K-S-L-E-I-E-E-K-I-N; and N-[AG]-H-[TA]-Y-H-I-N-S-I-S-[LIVM]-N-S-D.

Those skilled in the art will recognize, or be able to ascertain, using not more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such specific embodiments and equivalents are intended to be encompassed by the following claims.

All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Deposit Information. The following materials were deposited with the American Type Culture Collection (CMCC=Chiron Master Culture Collection).

TABLE 20 Cell Lines Deposited with ATCC ATCC Cell Line Deposit Date Accession No. CMCC Accession No. KM12L4-A Mar. 19, 1998 CRL-12496 11606 Km12C May 15, 1998 CRL-12533 11611 MDA-MB-231 May 15, 1998 CRL-12532 10583 MCF-7 Oct. 9, 1998 CRL-12584 10377

In addition, pools of selected clones, as well as libraries containing specific clones, were assigned an “ES” number (internal reference) and deposited with the ATCC. Table 21 below provides the ATCC Accession Nos. of the ES deposits, all of which were deposited on or before May 13, 1999. The names of the clones contained within each of these deposits are provided in the tables numbered 22 and greater (inserted before the claims).

TABLE 21 Pools of Clones and Libraries Deposited with ATCC on or before May 13, 1999 ATCC ATCC ES # Accession # ES # Accession # ES # ATCC Accession # 34 PTA-47 41 PTA-52 48 PTA-49 35 PTA-57 42 PTA-53 49 PTA-66 36 PTA-54 43 PTA-62 50 PTA-50 37 PTA-58 44 PTA-55 51 PTA-65 38 PTA-48 45 PTA-61 52 PTA-46 39 PTA-60 46 PTA-64 53 PTA-51 40 PTA-63 47 PTA-56 54 PTA-59

The deposits described herein are provided merely as convenience to those of skill in the art, and is not an admission that a deposit is required under 35 U.S.C. § 112. The sequence of the polynucleotides contained within the deposited material, as well as the amino acid sequence of the polypeptides encoded thereby, are incorporated herein by reference and are controlling in the event of any conflict with the written description of sequences herein. A license may be required to make, use, or sell the deposited material, and no such license is granted hereby.

Retrieval of Individual Clones from Deposit of Pooled Clones. Where the ATCC deposit is composed of a pool of cDNA clones or a library of cDNA clones, the deposit was prepared by first transfecting each of the clones into separate bacterial cells. The clones in the pool or library were then deposited as a pool of equal mixtures in the composite deposit. Particular clones can be obtained from the composite deposit using methods well known in the art. For example, a bacterial cell containing a particular clone can be identified by isolating single colonies, and identifying colonies containing the specific clone through standard colony hybridization techniques, using an oligonucleotide probe or probes designed to specifically hybridize to a sequence of the clone insert (e.g., a probe based upon unmasked sequence of the encoded polynucleotide having the indicated SEQ ID NO). The probe should be designed to have a T_(m) of approximately 80° C. (assuming 2° C. for each A or T and 4° C. for each G or C). Positive colonies can then be picked, grown in culture, and the recombinant clone isolated. Alternatively, probes designed in this manner can be used to PCR to isolate a nucleic acid molecule from the pooled clones according to methods well known in the art, e.g., by purifying the cDNA from the deposited culture pool, and using the probes in PCR reactions to produce an amplified product having the corresponding desired polynucleotide sequence.

TABLE 1A Priority Appln Information SEQ SEQ ID ID NO: Filed Dkt No. NO: Sequence Name Clone Name 1 May 14, 1998 1487 1 RTA00000608F.d.17.1 M00003981C:E04 2 May 14, 1998 1487 2 RTA00000589F.n.08.1 M00004182D:H03 3 May 14, 1998 1487 3 RTA00000589F.p.06.1 M00004223D:D07 4 May 14, 1998 1487 4 RTA00000597F.b.03.4 M00003770D:C07 5 May 14, 1998 1487 5 RTA00000608F.k.12.1 M00004029A:E01 6 May 14, 1998 1487 6 RTA00000585F.h.08.2 M00001432B:H08 7 May 14, 1998 1487 7 RTA00000585F.h.14.2 M00001433A:C07 8 May 14, 1998 1487 8 RTA00000609F.f.01.3 M00004060C:A02 9 May 14, 1998 1487 9 RTA00000588F.j.01.3 M00003835A:E03 10 May 14, 1998 1487 10 RTA00000596F.b.19.1 M00001663C:C03 11 May 14, 1998 1487 11 RTA00000585F.m.18.1 M00001444A:A09 12 May 14, 1998 1487 12 RTA00000596F.m.11.1 M00003753C:B01 13 May 14, 1998 1487 13 RTA00000589F.k.05.1 M00004133C:B02 14 May 14, 1998 1487 14 RTA00000589F.a.18.2 M00003984C:F04 15 May 14, 1998 1487 15 RTA00000585F.g.19.2 M00001431A:E05 16 May 14, 1998 1487 16 RTA00000595F.c 21.1 M00001598C:D10 17 May 14, 1998 1487 17 RTA00000584F.n.20.1 M00001406C:A11 18 May 14, 1998 1487 18 RTA00000611F.o.18.5 M00004204A:D04 19 May 14, 1998 1487 19 RTA00000597F.f.23.1 M00003787D:A06 20 May 14, 1998 1487 20 RTA00000585F.p.13.2 M00001452B:H06 21 May 14, 1998 1487 21 RTA00000583F.f.06.1 M00001348D:H08 22 May 14, 1998 1487 22 RTA00000585F.h.08.1 M00001432B:H08 23 May 14, 1998 1487 23 RTA00000589F.n.10.1 M00004184B:F11 24 May 14, 1998 1487 24 RTA00000614F.k.01.1 M00004465C:B12 25 May 14, 1998 1487 25 RTA00000587F.p.24.1 M00001584C:A03 26 May 14, 1998 1487 26 RTA00000587F.g.19.2 M00001548C:A09 27 May 14, 1998 1487 27 RTA00000612F.c.12.2 M00004222A:H10 28 May 14, 1998 1487 28 RTA00000589F.f.09.1 M00004064A:B12 29 May 14, 1998 1487 29 RTA00000586F.k.02.1 M00001490B:G04 30 May 14, 1998 1487 30 RTA00000609F.b.20.2 M00004050A:F02 31 May 14, 1998 1487 31 RTA00000584F.m.13.1 M00001402D:C07 32 May 14, 1998 1487 32 RTA00000614F.i.12.1 M00004447D:D10 33 May 14, 1998 1487 33 RTA00000608F.m.14.1 M00004035A:A10 34 May 14, 1998 1487 34 RTA00000608F.m.01.1 M00004033C:D10 35 May 14, 1998 1487 35 RTA00000597F.o.18.1 M00003819C:E04 36 May 14, 1998 1487 36 RTA00000584F.g.06.1 M00001390A:C06 37 May 14, 1998 1487 37 RTA00000609F.a.07.2 M00004046A:F04 38 May 14, 1998 1487 38 RTA00000607F.o.12.2 M00003961C:G02 39 May 14, 1998 1487 39 RTA00000597F.p.17.1 M00003821C:E04 40 May 14, 1998 1487 40 RTA00000609F.f.16.3 M00004063C:B11 41 May 14, 1998 1487 41 RTA00000584F.o.04.1 M00001407B:A08 42 May 14, 1998 1487 42 RTA00000608F.d.21.1 M00003982A:G03 43 May 14, 1998 1487 43 RTA00000614F.b.23.1 M00004389C:E01 44 May 14, 1998 1487 44 RTA00000612F.1.04.1 M00004268C:F08 45 May 14, 1998 1487 45 RTA00000611F.n.20.3 M00004200D:A07 46 May 14, 1998 1487 46 RTA00000608F.e.01.1 M00003982B:C10 47 May 14, 1998 1487 47 RTA00000585F.k.21.1 M00001439C:G06 48 May 14, 1998 1487 48 RTA00000589F.d.07.1 M00004037B:A09 49 May 14, 1998 1487 49 RTA00000614F.j.07.1 M00004460B:H09 50 May 14, 1998 1487 50 RTA00000614F.o.08.1 M00004508B:G02 51 May 14, 1998 1487 51 RTA00000608F.e.11.1 M00003983C:E07 52 May 14, 1998 1487 52 RTA00000589F.d.08.1 M00004037B:B05 53 May 14, 1998 1487 53 RTA00000614F.1.09.1 M00004491D:D07 54 May 14, 1998 1487 54 RTA00000607F.m.15.1 M00003949B:D05 55 May 14, 1998 1487 55 RTA00000609F.p.17.1 M00004093D:D09 56 May 14, 1998 1487 56 RTA00000583F.d.22.1 M00001346B:G03 57 May 14, 1998 1487 57 RTA00000589F.h.07.1 M00004081B:C11 58 May 14, 1998 1487 58 RTA00000611F.k.19.3 M00004191B:G01 59 May 14, 1998 1487 59 RTA00000595F.p.10.1 M00001654D:F06 60 May 14, 1998 1487 60 RTA00000609F.h.01.1 M00004068D:B01 61 May 14, 1998 1487 61 RTA00000612F.g.24.2 M00004244B:A02 62 May 14, 1998 1487 62 RTA00000608F.b.10.1 M00003975B:H09 63 May 14, 1998 1487 63 RTA00000587F.j.12.1 M00001555D:F11 64 May 14, 1998 1487 64 RTA00000610F.p.02.1 M00004152C:E01 65 May 14, 1998 1487 65 RTA00000608F.f.15.2 M00003987A:C07 66 May 14, 1998 1487 66 RTA00000614F.k.11.1 M00004467D:F09 67 May 14, 1998 1487 67 RTA00000612F.b.10.2 M00004216D:E10 68 May 14, 1998 1487 68 RTA00000606F.k.11.1 M00003864B:A04 69 May 14, 1998 1487 69 RTA00000583F.g.18.1 M00001352C:E01 70 May 14, 1998 1487 70 RTA00000585F.i.13.1 M00001435A:F03 71 May 14, 1998 1487 71 RTA00000612F.g.11.2 M00004240D:A07 72 May 14, 1998 1487 72 RTA00000607F.1.05.1 M00003936C:F10 73 May 14, 1998 1487 73 RTA00000610F.a.11.1 M00004097C:A03 74 May 14, 1998 1487 74 RTA00000596F.k.09.1 M00003746B:E12 75 May 14, 1998 1487 75 RTA00000611F.d.11.1 M00004169A:B11 76 May 14, 1998 1487 76 RTA00000588F.g.06.1 M00003797D:E10 77 May 14, 1998 1487 77 RTA00000595F.n.15.1 M00001648C:F06 78 May 14, 1998 1487 78 RTA00000584F.c.22.1 M00001382C:C09 79 May 14, 1998 1487 79 RTA00000585F.1.17.1 M00001441D:H05 80 May 14, 1998 1487 80 RTA00000608F.k.15.2 M00004029C:B03 81 May 14, 1998 1487 81 RTA00000597F.g.14.1 M00003789C:E03 82 May 14, 1998 1487 82 RTA00000588F.n.16.3 M00003906C:H12 83 May 14, 1998 1487 83 RTA00000606F.o.14.1 M00003886C:D10 84 May 14, 1998 1487 84 RTA00000608F.n.09.1 M00004037A:A07 85 May 14, 1998 1487 85 RTA00000613F.h.06.1 M00004329C:F11 86 May 14, 1998 1487 86 RTA00000587F.1.08.1 M00001564C:D04 87 May 14, 1998 1487 87 RTA0000059OF.d.23.1 M00004350B:F06 88 May 14, 1998 1487 88 RTA00000609F.i.24.2 M00004073D:E01 89 May 14, 1998 1487 89 RTA00000614F.j.23.1 M00004465C:B10 90 May 14, 1998 1487 90 RTA00000587F.p.15.1 M00001582D:B10 91 May 14, 1998 1487 91 RTA00000640F.a.05.1 M00004190A:A09 92 May 14, 1998 1487 92 RTA00000609F.k.01.2 M00004077D:D10 93 May 14, 1998 1487 93 RTA00000589F.e.14.2 M00004054D:D02 94 May 14, 1998 1487 94 RTA00000586F.a.13.1 M00001455A:E09 95 May 14, 1998 1487 95 RTA00000590F.d.10.1 M00004337D:G08 96 May 14, 1998 1487 96 RTA00000608F.i.18.1 M00003998A:D03 97 May 14, 1998 1487 97 RTA00000608F.m.05.1 M00004034A:E08 98 May 14, 1998 1487 98 RTA00000597F.p.10.1 M00003820D:E02 99 May 14, 1998 1487 99 RTA00000585F.n.20.1 M00001446D:B10 100 May 14, 1998 1487 100 RTA00000584F.a.14.1 M00001377A:D03 101 May 14, 1998 1487 101 RTA00000609F.p.03.2 M00004092A:C03 102 May 14, 1998 1487 102 RTA00000606F.f.06.1 M00003841A:E09 103 May 14, 1998 1487 103 RTA00000609F.o.22.1 M00004091D:D09 104 May 14, 1998 1487 104 RTA00000587F.d.02.1 M00001537B:C12 105 May 14, 1998 1487 105 RTA00000612F.n.07.2 M00004277C:H11 106 May 14, 1998 1487 106 RTA00000606F.p.03.1 M00003888C:E01 107 May 14, 1998 1487 107 RTA00000589F.g.15.1 M00004076D:B03 108 May 14, 1998 1487 108 RTA00000610F.b.09.1 M00004102C:F07 109 May 14, 1998 1487 109 RTA00000603F.a.13.1 M00003820C:A09 110 May 14, 1998 1487 110 RTA00000606F.o.01.1 M00003883D:C03 111 May 14, 1998 1487 111 RTA00000589F.c.17.1 M00004030B:C05 112 May 14, 1998 1487 112 RTA00000589F.k.22.1 M00004140B:B01 113 May 14, 1998 1487 113 RTA00000585F.k.08.1 M00001438C:H05 114 May 14, 1998 1487 114 RTA00000595F.a.09.1 M00001586A:F09 115 May 14, 1998 1487 115 RTA00000597F.g.22.1 M00003790B:F12 116 May 14, 1998 1487 116 RTA00000597F.c.02.3 M00003773A:C09 117 May 14, 1998 1487 117 RTA00000587F.b.18.1 M00001530A:D11 118 May 14, 1998 1487 118 RTA00000606F.a.18.1 M00003824B:D06 119 May 14, 1998 1487 119 RTA00000612F.j.14.2 M00004260A:B07 120 May 14, 1998 1487 120 RTA00000612F.g.23.3 M00004243C:E10 121 May 14, 1998 1487 121 RTA00000583F.p.05.1 M00001374C:C09 122 May 14, 1998 1487 122 RTA00000586F.a.12.1 M00001455A:C03 123 May 14, 1998 1487 123 RTA00000613F.d.21.1 M00004308A:E06 124 May 14, 1998 1487 124 RTA00000586F.e.02.2 M00001466C:F02 125 May 14, 1998 1487 125 RTA00000595F.f.07.1 M00001609A:B12 126 May 14, 1998 1487 126 RTA00000607F.o.13.2 M00003962B:B09 127 May 14, 1998 1487 127 RTA00000595F.b.06.1 M00001590D:A07 128 May 14, 1998 1487 128 RTA00000609F.1.04.2 M00004081C:A01 129 May 14, 1998 1487 129 RTA00000610F.b.08.1 M00004102B:B04 130 May 14, 1998 1487 130 RTA00000585F.k.06.1 M00001438B:H06 131 May 14, 1998 1487 131 RTA00000611F.o.20.5 M00004204B:A04 132 May 14, 1998 1487 132 RTA00000614F.g.09.1 M00004421A:G04 133 May 14, 1998 1487 133 RTA00000597F.h.12.1 M00003793C:D11 134 May 14, 1998 1487 134 RTA00000597F.p.21.1 M00003822A:G05 135 May 14, 1998 1487 135 RTA00000595F.1.24.2 M00001641B:G05 136 May 14, 1998 1487 136 RTA00000584F.1.05.1 M00001399C:E10 137 May 14, 1998 1487 137 RTA00000586F.j.16.1 M00001489B:F08 138 May 14, 1998 1487 138 RTA00000613F.h.20.1 M00004332B:E11 139 May 14, 1998 1487 139 RTA00000606F.k.06.1 M00003862C:H10 140 May 14, 1998 1487 140 RTA00000587F.j.01.1 M00001557C:B08 141 May 14, 1998 1487 141 RTA00000610F.1.23.1 M00004143A:H07 142 May 14, 1998 1487 142 RTA00000606F.j.21.1 M00003860B:A07 143 May 14, 1998 1487 143 RTA00000608F.j.15.1 M00003997D:D07 144 May 14, 1998 1487 144 RTA00000596F.o.21.1 M00003763D:F06 145 May 14, 1998 1487 145 RTA00000597F.1.05.1 M00003809B:D08 146 May 14, 1998 1487 146 RTA00000608F.h.04.1 M00003992D:G01 147 May 14, 1998 1487 147 RTA00000585F.d.21.1 M00001424A:H09 148 May 14, 1998 1487 148 RTA00000606F.k.15.1 M00003864C:D09 149 May 14, 1998 1487 149 RTA00000612F.k.16.2 M00004266A:F10 150 May 14, 1998 1487 150 RTA00000589F.b.14.1 M00003991B:B05 151 May 14, 1998 1487 151 RTA00000597F.m.17.1 M00003813D:A06 152 May 14, 1998 1487 152 RTA00000585F.k.14.1 M00001439B:E02 153 May 14, 1998 1487 153 RTA00000584F.f.21.1 M00001389B:B06 154 May 14, 1998 1487 154 RTA00000597F.i.09.1 M00003796C:H03 155 May 14, 1998 1487 155 RTA00000597F.h.20.1 M00003795A:B01 156 May 14, 1998 1487 156 RTA00000608F.k.24.1 M00004030B:B02 157 May 14, 1998 1487 157 RTA00000586F.n.05.1 M00001500B:H07 158 May 14, 1998 1487 158 RTA00000608F.n.02.1 M00004035D:E04 159 May 14, 1998 1487 159 RTA00000585F.e.11.2 M00001425C:E10 160 May 14, 1998 1487 160 RTA00000596F.k.08.1 M00003746A:E01 161 May 14, 1998 1487 161 RTA00000611F.b.14.1 M00004163A:D11 162 May 14, 1998 1487 162 RTA00000607F.m.10.1 M00003948B:B03 163 May 14, 1998 1487 163 RTA00000586F.p.01.1 M00001506A:F01 164 May 14, 1998 1487 164 RTA00000589F.g.08.1 M00004075C:C09 165 May 14, 1998 1487 165 RTA00000608F.n.19.1 M00004037D:B05 166 May 14, 1998 1487 166 RTA00000607F.c.16.2 M00003905C:B01 167 May 14, 1998 1487 167 RTA00000595F.j.09.1 M00001622C:F06 168 May 14, 1998 1487 168 RTA00000584F.j.10.1 M00001397B:E02 169 May 14, 1998 1487 169 RTA00000589F.i.13.1 M00004103B:C07 170 May 14, 1998 1487 170 RTA00000585F.f.04.2 M00001427A:C05 171 May 14, 1998 1487 171 RTA00000606F.d.24.1 M00003837C:F05 172 May 14, 1998 1487 172 RTA00000609F.n.22.1 M00004088A:F12 173 May 14, 1998 1487 173 RTA00000610F.m.14.1 M00004144D:B06 174 May 14, 1998 1487 174 RTA00000606F.k.17.1 M00003864D:G05 175 May 14, 1998 1487 175 RTA00000583F.d.06.1 M00001345A:A12 176 May 14, 1998 1487 176 RTA00000608F.m.09.1 M00004034C:F05 177 May 14, 1998 1487 177 RTA00000608F.o.17.1 M00004040D:B05 178 May 14, 1998 1487 178 RTA00000583F.k.15.3 M00001362B:H09 179 May 14, 1998 1487 179 RTA00000610F.f.16.1 M00004120A:C02 180 May 14, 1998 1487 180 RTA00000608F.h.19.2 M00003994C:C11 181 May 14, 1998 1487 181 RTA00000584F.m.07.1 M00001401D:D04 182 May 14, 1998 1487 182 RTA00000587F.h.20.2 M00001552B:D01 183 May 14, 1998 1487 183 RTA00000596F.b.01.1 M00001660A:F10 184 May 14, 1998 1487 184 RTA00000611F.n.13.2 M00004199D:C02 185 May 14, 1998 1487 185 RTA00000597F.o.06.1 M00003818A:F09 186 May 14, 1998 1487 186 RTA00000589F.n.03.1 M00004178B:F06 187 May 14, 1998 1487 187 RTA00000597F.k.07.1 M00003805A:G05 188 May 14, 1998 1487 188 RTA00000611F.c.19.2 M00004166B:E10 189 May 14, 1998 1487 189 RTA00000606F.1.12.1 M00003868D:F02 190 May 14, 1998 1487 190 RTA00000614F.d.22.1 M00004407D:B09 191 May 14, 1998 1487 191 RTA00000608F.n.16.1 M00004037C:D07 192 May 14, 1998 1487 192 RTA00000595F.1.20.2 M00001640D:C10 193 May 14, 1998 1487 193 RTA00000608F.k.22.1 M00004030A:E09 194 May 14, 1998 1487 194 RTA00000583F.h.23.1 M00001355B:A01 195 May 14, 1998 1487 195 RTA00000608F.c.23.1 M00003980C:A11 196 May 14, 1998 1487 196 RTA00000585F.n 01.1 M00001444A:G12 197 May 14, 1998 1487 197 RTA00000596F.n.08.1 M00003756C:C08 198 May 14, 1998 1487 198 RTA00000612F.d.16.2 M00004229C:G11 199 May 14, 1998 1487 199 RTA00000589F.c.19.1 M00004031A:B04 200 May 14, 1998 1487 200 RTA00000584F.j.08.1 M00001397A:F10 201 May 14, 1998 1487 201 RTA00000583F.j.03.3 M00001358D:D09 202 May 14, 1998 1487 202 RTA00000597F.j.09.1 M00003801D:F05 203 May 14, 1998 1487 203 RTA00000614F.n.21.1 M00004506C:H10 204 May 14, 1998 1487 204 RTA00000606F.d.05.1 M00003833B:A11 205 May 14, 1998 1487 205 RTA00000589F.d.10.1 M00004038C:D12 206 May 14, 1998 1487 206 RTA00000597F.p.01.1 M00003820A:H04 207 May 14, 1998 1487 207 RTA00000586F.1.20.1 M00001496A:B03 208 May 14, 1998 1487 208 RTA00000607F.c.07.2 M00003903C:A12 209 May 14, 1998 1487 209 RTA00000595F.b.02.1 M00001589C:D12 210 May 14, 1998 1487 210 RTA00000597F.n.18.1 M00003816C:F10 211 May 14, 1998 1487 211 RTA00000612F.d.10.2 M00004228C:D11 212 May 14, 1998 1487 212 RTA00000609F.n.13.1 M00004086D:A07 213 May 14, 1998 1487 213 RTA00000610F.b.02.1 M00004101D:A03 214 May 14, 1998 1487 214 RTA00000590F.a.17.1 M00004249C:E12 215 May 14, 1998 1487 215 RTA00000587F.i.02.1 M00001553D:B06 216 May 14, 1998 1487 216 RTA00000583F.p.22.1 M00001376A:H02 217 May 14, 1998 1487 217 RTA00000609F.d.08.1 M00004054D:A03 218 May 14, 1998 1487 218 RTA00000609F.k.06.2 M00004078C:A08 219 May 14, 1998 1487 219 RTA00000585F.i.20.1 M00001435B:G10 220 May 14, 1998 1487 220 RTA00000585F.e.15.2 M00001426A:F09 221 May 14, 1998 1487 221 RTA00000595F.c.18.1 M00001597C:B03 222 May 14, 1998 1487 222 RTA00000596F.p.18.1 M00003766A:G09 223 May 14, 1998 1487 223 RTA00000611F.1.04.3 M00004193A:C07 224 May 14, 1998 1487 224 RTA00000614F.o.06.1 M00004508A:G12 225 May 14, 1998 1487 225 RTA00000586F.o.13.1 M00001504D:D09 226 May 14, 1998 1487 226 RTA00000612F.o.21.1 M00004283C:D03 227 May 14, 1998 1487 227 RTA00000585F.k.18.1 M00001439C:A01 228 May 14, 1998 1487 228 RTA00000611F.o.19.5 M00004204A:D10 229 May 14, 1998 1487 229 RTA00000611F.1.10.3 M00004193C:H01 230 May 14, 1998 1487 230 RTA00000612F.b.22.2 M00004217D:G10 231 May 14, 1998 1487 231 RTA00000583F.n.06.1 M00001370B:B12 232 May 14, 1998 1487 232 RTA00000611F.p.08.3 M00004206C:G11 233 May 14, 1998 1487 233 RTA00000607F.e.03.2 M00003909D:G01 234 May 14, 1998 1487 234 RTA00000607F.b.09.2 M00003896D:B01 235 May 14, 1998 1487 235 RTA00000585F.j.16.1 M00001436D:C10 236 May 14, 1998 1487 236 RTA00000607F.g.05.2 M00003915C:G01 237 May 14, 1998 1487 237 RTA00000586F.o.14.1 M00001505A:E09 238 May 14, 1998 1487 238 RTA00000607F.h.15.1 M00003920B:A10 239 May 14, 1998 1487 239 RTA00000586F.m.14.1 M00001499B:H05 240 May 14, 1998 1487 240 RTA00000610F.p.17.1 M00004154D:F11 241 May 14, 1998 1487 241 RTA00000584F.d.11.1 M00001383C:C07 242 May 14, 1998 1487 242 RTA00000610F.e.07.1 M00004114C:F02 243 May 14, 1998 1487 243 RTA00000610F.b.17.1 M00004103B:C09 244 May 14, 1998 1487 244 RTA00000596F.c.05.1 M00001669A:H11 245 May 14, 1998 1487 245 RTA00000586F.b.17.1 M00001458B:F06 246 May 14, 1998 1487 246 RTA00000607F.1.16.1 M00003939A:A02 247 May 14, 1998 1487 247 RTA00000590F.f.18.2 M00004446A:G01 248 May 14, 1998 1487 248 RTA00000603F.b.07.1 M00004242C:C01 249 May 14, 1998 1487 249 RTA00000589F.f.11.1 M00004066A:E12 250 May 14, 1998 1487 250 RTA00000589F.j.09.1 M00004115A:G09 251 May 14, 1998 1487 251 RTA00000583F.a.18.1 M00001339B:E05 252 May 14, 1998 1487 252 RTA00000612F.f.23.3 M00004239C:C09 253 May 14, 1998 1487 253 RTA00000597F.0.12.1 M00003818C:E09 254 May 14, 1998 1487 254 RTA00000607F.b.05.2 M00003896B:F08 255 May 14, 1998 1487 255 RTA00000607F.e.23.2 M00003912C:C11 256 May 14, 1998 1487 256 RTA00000586F.m.11.1 M00001499A:D05 257 May 14, 1998 1487 257 RTA00000585F.g.18.2 M00001431A:C10 258 May 14, 1998 1487 258 RTA00000614F.d.07.1 M00004403A:B05 259 May 14, 1998 1487 259 RTA00000606F.c.23.1 M00003832B:G03 260 May 14, 1998 1487 260 RTA00000609F.d.13.1 M00004055B:F06 261 May 14, 1998 1487 261 RTA00000606F.c.04.1 M00003829A:E02 262 May 14, 1998 1487 262 RTA00000587F.f.02.1 M00001542C:F06 263 May 14, 1998 1487 263 RTA00000585F.e.14.2 M00001426A:C02 264 May 14, 1998 1487 264 RTA00000584F.o.03.2 M00001406D:H01 265 May 14, 1998 1487 265 RTA00000614F.m.24.1 M00004501A:G06 266 May 14, 1998 1487 266 RTA00000586F.j.21.1 M00001489D:C08 267 May 14, 1998 1487 267 RTA00000585F.d.02.2 M00001421C:A03 268 May 14, 1998 1487 268 RTA00000597F.o.19.1 M00003819D:G09 269 May 14, 1998 1487 269 RTA00000613F.h.02.1 M00004328A:H06 270 May 14, 1998 1487 270 RTA00000612F.m.08.2 M00004273D:E11 271 May 14, 1998 1487 271 RTA00000606F.g.04.1 M00003844C:H05 272 May 14, 1998 1487 272 RTA00000608F.h.04.2 M00003992D:G01 273 May 14, 1998 1487 273 RTA00000609F.e.19.3 M00004059A:G09 274 May 14, 1998 1487 274 RTA00000613F.c.10.1 M00004297D:B08 275 May 14, 1998 1487 275 RTA00000587F.d.24.1 M00001539B:B01 276 May 14, 1998 1487 276 RTA00000597F.a.22.5 M00003769D:G12 277 May 14, 1998 1487 277 RTA00000595F.m.11.1 M00001644D:F09 278 May 14, 1998 1487 278 RTA00000613F.k.05.1 M00004346B:D06 279 May 14, 1998 1487 279 RTA00000611F.n.15.2 M00004200A:G06 280 May 14, 1998 1487 280 RTA00000609F.m.20.2 M00004085B:G06 281 May 14, 1998 1487 281 RTA00000609F.c.08.1 M00004051C:D10 282 May 14, 1998 1487 282 RTA00000586F.k.13.1 M00001491C:C01 283 May 14, 1998 1487 283 RTA00000595F.i.16.1 M00001623D:A09 284 May 14, 1998 1487 284 RTA00000588F.j.17.3 M00003839D:G06 285 May 14, 1998 1487 285 RTA00000610F.j.05.1 M00004129A:H08 286 May 14, 1998 1487 286 RTA00000596F.o.14.1 M00003762A:D11 287 May 14, 1998 1487 287 RTA00000583F.e.15.1 M00001347B:H01 288 May 14, 1998 1487 288 RTA00000584F.a.01.2 M00001376B:C11 289 May 14, 1998 1487 289 RTA00000597F.c.10.4 M00003773D:C02 290 May 14, 1998 1487 290 RTA00000595F.d.20.1 M00001604B:D09 291 May 14, 1998 1487 291 RTA00000609F.m.04.2 M00004084A:D11 292 May 14, 1998 1487 292 RTA00000589F.b.08.1 M00003988C:A06 293 May 14, 1998 1487 293 RTA00000583F.k.13.3 M00001362B:A09 294 May 14, 1998 1487 294 RTA00000606F.b.07.1 M00003825C:B02 295 May 14, 1998 1487 295 RTA00000583F.a.17.1 M00001339B:A03 296 May 14, 1998 1487 296 RTA00000611F.o.09.5 M00004201D:E12 297 May 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14, 1998 1487 346 RTA00000609F.j.05.3 M00004075A:G10 347 May 14, 1998 1487 347 RTA00000586F.d.01.1 M00001463C:A01 348 May 14, 1998 1487 348 RTA00000612F.h.03.3 M00004245A:G09 349 May 14, 1998 1487 349 RTA00000596F.e.18.2 M00001678D:A12 350 May 14, 1998 1487 350 RTA00000606F.g.18.1 M00003846B:H02 351 May 14, 1998 1487 351 RTA00000597F.c.07.4 M00003773B:G08 352 May 14, 1998 1487 352 RTA00000610F.e.15.1 M00004117B:F01 353 May 14, 1998 1487 353 RTA00000595F.h.07.1 M00001618C:E06 354 May 14, 1998 1487 354 RTA00000597F.f.17.1 M00003786D:C06 355 May 14, 1998 1487 355 RTA00000606F.l.10.1 M00003868B:C07 356 May 14, 1998 1487 356 RTA00000586F.g.20.1 M00001478A:B06 357 May 14, 1998 1487 357 RTA00000606F.b.05.1 M00003825B:D12 358 May 14, 1998 1487 358 RTA00000588F.p.09.2 M00003972B:A11 359 May 14, 1998 1487 359 RTA00000595F.d.05.1 M00001599A:H09 360 May 14, 1998 1487 360 RTA00000587F.n.19.1 M00001572C:E07 361 May 14, 1998 1487 361 RTA00000590F.a.02.1 M00004240D:E06 362 May 14, 1998 1487 362 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14, 1998 1487 395 RTA00000597F.l.18.1 M00003811B:E07 396 May 14, 1998 1487 396 RTA00000585F.h.03.2 M00001432A:F12 397 May 14, 1998 1487 397 RTA00000607F.h.23.1 M00003920D:D09 398 May 14, 1998 1487 398 RTA00000607F.f.23.2 M00003915B:G07 399 May 14, 1998 1487 399 RTA00000607F.f.18.2 M00003915A:D09 400 May 14, 1998 1487 400 RTA00000609F.i.23.2 M00004073D:B11 401 May 14, 1998 1487 401 RTA00000612F.f.05.3 M00004236D:F04 402 May 14, 1998 1487 402 RTA00000597F.o.07.1 M00003818B:A01 403 May 14, 1998 1487 403 RTA00000611F.o.06.5 M00004201D:C11 404 May 14, 1998 1487 404 RTA00000589F.e.05.2 M00004051C:D02 405 May 14, 1998 1487 405 RTA00000584F.o.07.1 M00001407D:H11 406 May 14, 1998 1487 406 RTA00000608F.e.06.1 M00003983A:D02 407 May 14, 1998 1487 407 RTA00000595F.a.22.1 M00001588D:H08 408 May 14, 1998 1487 408 RTA00000611F.c.03.2 M00004164D:D02 409 May 14, 1998 1487 409 RTA00000585F.c.03.2 M00001418A:C02 410 May 14, 1998 1487 410 RTA00000611F.b.07.1 M00004161B:A12 411 May 14, 1998 1487 411 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14, 1998 1487 444 RTA00000607F.p.01.2 M00003965A:F07 445 May 14, 1998 1487 445 RTA00000611F.c.16.2 M00004166A:F02 446 May 14, 1998 1487 446 RTA00000611F.b.01.1 M00004159D:H07 447 May 14, 1998 1487 447 RTA00000612F.b.12.2 M00004217A:A11 448 May 14, 1998 1487 448 RTA00000584F.h.09.1 M00001391D:A09 449 May 14, 1998 1487 449 RTA00000612F.g.18.3 M00004242C:C02 450 May 14, 1998 1487 450 RTA00000609F.b.18.2 M00004049D:G04 451 May 14, 1998 1487 451 RTA00000608F.f.17.1 M00003987D:F06 452 May 14, 1998 1487 452 RTA00000589F.e.21.2 M00004058B:F12 453 May 14, 1998 1487 453 RTA00000606F.j.07.1 M00003857C:A03 454 May 14, 1998 1487 454 RTA00000610F.b.21.1 M00004103C:F11 455 May 14, 1998 1487 455 RTA00000611F.c.22.2 M00004166D:G07 456 May 14, 1998 1487 456 RTA00000583F.d.04.1 M00001344D:G11 457 May 14, 1998 1487 457 RTA00000610F.h.08.1 M00004126B:G02 458 May 14, 1998 1487 458 RTA00000596F.a.06.1 M00001658B:C07 459 May 14, 1998 1487 459 RTA00000612F.o.10.2 M00004281B:B05 460 May 14, 1998 1487 460 RTA00000610F.l.22.1 M00004143A:G12 461 May 14, 1998 1487 461 RTA00000612F.o.09.2 M00004281B:B03 462 May 14, 1998 1487 462 RTA00000596F.f.09.2 M00001681A:H09 463 May 14, 1998 1487 463 RTA00000607F.p.13.2 M00003970A:G10 464 May 14, 1998 1487 464 RTA00000610F.e.11.1 M00004115C:H04 465 May 14, 1998 1487 465 RTA00000611F.b.02.1 M00004160A:A01 466 May 14, 1998 1487 466 RTA00000608F.j.24.1 M00004027C:H01 467 May 14, 1998 1487 467 RTA00000614F.k.22.1 M00004470C:A02 468 May 14, 1998 1487 468 RTA00000612F.h.09.3 M00004247A:E01 469 May 14, 1998 1487 469 RTA00000587F.f.01.1 M00001542C:D10 470 May 14, 1998 1487 470 RTA00000608F.d.04.1 M00003980C:G10 471 May 14, 1998 1487 471 RTA00000585F.m.16.2 M00001443D:C03 472 May 14, 1998 1487 472 RTA00000613F.c.17.1 M00004298B:D04 473 May 14, 1998 1487 473 RTA00000613F.h.19.1 M00004332B:D02 474 May 14, 1998 1487 474 RTA00000609F.d.07.1 M00004054B:G02 475 May 14, 1998 1487 475 RTA00000606F.0.17.1 M00003887B:C03 476 May 14, 1998 1487 476 RTA00000585F.n.10.1 M00001445B:E03 477 May 14, 1998 1487 477 RTA00000612F.p.04.2 M00004284B:F07 478 May 14, 1998 1487 478 RTA00000589F.c.02.1 M00003997B:H04 479 May 14, 1998 1487 479 RTA00000608F.p.16.1 M00004044A:F08 480 May 14, 1998 1487 480 RTA00000597F.n.12.1 M00003815D:D01 481 May 14, 1998 1487 481 RTA00000608F.l.10.1 M00004031A:G05 482 May 14, 1998 1487 482 RTA00000606F.o.05.1 M00003884D:A12 483 May 14, 1998 1487 483 RTA00000587F.j.05.1 M00001558B:A12 484 May 14, 1998 1487 484 RTA00000584F.d.15.1 M00001384A:C09 485 May 14, 1998 1487 485 RTA00000612F.n.22.1 M00004279D:E02 486 May 14, 1998 1487 486 RTA00000585F.m.13.2 M00001443D:A01 487 May 14, 1998 1487 487 RTA00000586F.m.22.1 M00001500A:D09 488 May 14, 1998 1487 488 RTA00000608F.i.17.1 M00003997D:G11 489 May 14, 1998 1487 489 RTA00000614F.k.04.1 M00004466A:E09 490 May 14, 1998 1487 490 RTA00000608F.n.15.1 M00004037C:C05 491 May 14, 1998 1487 491 RTA00000610F.m.06.1 M00004143C:F08 492 May 14, 1998 1487 492 RTA00000585F.d.12.2 M00001422D:D02 493 May 14, 1998 1487 493 RTA00000608F.b.19.1 M00003976D:D12 494 May 14, 1998 1487 494 RTA00000596F.k.06.1 M00003745C:E03 495 May 14, 1998 1487 495 RTA00000609F.o.14.2 M00004091A:E01 496 May 14, 1998 1487 496 RTA00000607F.m.14.1 M00003949B:A08 497 May 14, 1998 1487 497 RTA00000606F.f.08.1 M00003841B:D05 498 May 14, 1998 1487 498 RTA00000583F.l.14.3 M00001365D:D12 499 May 14, 1998 1487 499 RTA00000614F.g.04.1 M00004419D:G01 500 May 14, 1998 1487 500 RTA00000610F.m.21.1 M00004145C:A03 501 May 14, 1998 1487 501 RTA00000585F.d.16.1 M00001423C:D06 502 May 14, 1998 1487 502 RTA00000588F.o.05.2 M00003918C:E07 503 May 14, 1998 1487 503 RTA00000585F.b.04.3 M00001415D:E12 504 May 14, 1998 1487 504 RTA00000588F.d.21.1 M00001687C:A06 505 May 14, 1998 1487 505 RTA00000595F.g.16.1 M00001614C:G04 506 May 14, 1998 1487 506 RTA00000612F.i.18.2 M00004253B:F06 507 May 14, 1998 1487 507 RTA00000612F.e.12.1 M00004234B:G06 508 May 14, 1998 1487 508 RTA00000583F.p.08.1 M00001374D:D09 509 May 14, 1998 1487 509 RTA00000608F.b.04.1 M00003974C:A05 510 May 14, 1998 1487 510 RTA00000596F.l.07.1 M00003749B:C08 511 May 14, 1998 1487 511 RTA00000597F.l.02.1 M00003809A:H12 512 May 14, 1998 1487 512 RTA00000595F.j.05.1 M00001626C:C10 513 May 14, 1998 1487 513 RTA00000586F.k.18.1 M00001491D:E07 514 May 14, 1998 1487 514 RTA00000608F.p.07.1 M00004041D:E06 515 May 14, 1998 1487 515 RTA00000596F.m.07.1 M00003752D:D09 516 May 14, 1998 1487 516 RTA00000588F.l.20.2 M00003859C:B09 517 May 14, 1998 1487 517 RTA00000614F.a.20.1 M00004383A:F02 518 May 14, 1998 1487 518 RTA00000597F.i.20.1 M00003799B:D02 519 May 14, 1998 1487 519 RTA00000611F.n.143 M00004200A:A09 520 May 14, 1998 1487 520 RTA00000586F.m.10.1 M00001499A:D01 521 May 14, 1998 1487 521 RTA00000607F.i.06.4 M00003921D:C06 522 May 14, 1998 1487 522 RTA00000585F.p.19.2 M00001453B:F08 523 May 14, 1998 1487 523 RTA00000583F.c.06.1 M00001342C:A04 524 May 14, 1998 1487 524 RTA00000595F.p.20.1 M00001656D:F11 525 May 14, 1998 1487 525 RTA00000606F.g.02.1 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RTA00000615F.f.10.1 M00004999A:F1 839 May 15, 1998 1488 88 RTA00000615F.b.19.1 M00004845D:E11 840 May 15, 1998 1488 89 RTA00000626F.a.07.1 M00006626A:G11 841 May 15, 1998 1488 90 RTA00000592F.b.20.1 M00005685B:D8 842 May 15, 1998 1488 91 RTA00000622F.p.16.1 M00007100C:D1 843 May 15, 1998 1488 92 RTA00000620F.a.16.1 M00006834A:C8 844 May 15, 1998 1488 93 RTA00000623F.e.21.1 M00007130B:B3 845 May 15, 1998 1488 94 RTA00000619F.k.05.1 M00006805A:E11 846 May 15, 1998 1488 95 RTA00000626F.c.10.1 M00006636D:A5 847 May 15, 1998 1488 96 RTA00000619F.i.13.1 M00006791B:B8 848 May 15, 1998 1488 97 RTA00000620F.k.22.1 M00006895D:E10 849 May 15, 1998 1488 98 RTA00000617F.a.17.1 M00005450D:D2 850 May 15, 1998 1488 99 RTA00000617F.c.18.1 M00005457D:C8 851 May 15, 1998 1488 100 RTA00000626F.g.12.1 M00006664B:B4 852 May 15, 1998 1488 101 RTA00000617F.j.11.1 M00005489A:F6 853 May 15, 1998 1488 102 RTA00000621F.c.11.1 M00006936B:E9 854 May 15, 1998 1488 103 RTA00000623F.f.12.1 M00007134B:G7 855 May 15, 1998 1488 104 RTA00000626F.g.17.1 M00006665A:F7 856 May 15, 1998 1488 105 RTA00000619F.o.06.4 M00006823D:D12 857 May 15, 1998 1488 106 RTA00000625F.j.10.1 M00005837A:D12 858 May 15, 1998 1488 107 RTA00000620F.k.12.1 M00006893C:F2 859 May 15, 1998 1488 108 RTA00000625F.j.06.1 M00005828D:C9 860 May 15, 1998 1488 109 RTA00000616F.b.12.1 M00005378A:A8 861 May 15, 1998 1488 110 RTA00000620F.d.04.1 M00006850C:G7 862 May 15, 1998 1488 111 RTA00000624F.n.20.1 M00005655D:C4 863 May 15, 1998 1488 112 RTA00000620F.m.14.1 M00006907C:D3 864 May 15, 1998 1488 113 RTA00000625F.m.15.1 M00006596D:H4 865 May 15, 1998 1488 114 RTA00000619F.g.19.1 M00006779D:D3 866 May 15, 1998 1488 115 RTA00000626F.b.10.1 M00006633D:A6 867 May 15, 1998 1488 116 RTA00000618F.c.23.1 M00006679C:D7 868 May 15, 1998 1488 117 RTA00000591F.o.17.1 M00005616B:D5 869 May 15, 1998 1488 118 RTA00000615F.b.23.1 M00004846D:H9 870 May 15, 1998 1488 119 RTA00000616F.e.20.1 M00005394A:G7 871 May 15, 1998 1488 120 RTA00000625F.b.23.1 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137 RTA00000625F.h.18.1 M00005813D:F6 889 May 15, 1998 1488 138 RTA00000622F.p.17.1 M00007101A:A11 890 May 15, 1998 1488 139 RTA00000620F.d.08.1 M00006851C:H9 891 May 15, 1998 1488 140 RTA00000621F.i.14.2 M00006966B:B9 892 May 15, 1998 1488 141 RTA00000625F.j.19.1 M00006576D:F11 893 May 15, 1998 1488 142 RTA00000618F.o.23.1 M00006737C:A8 894 May 15, 1998 1488 143 RTA00000618F.m.12.1 M00006725A:B3 895 May 15, 1998 1488 144 RTA00000625F.o.19.1 M00006616D:C8 896 May 15, 1998 1488 145 RTA00000619F.a.18.1 M00006744C:C6 897 May 15, 1998 1488 146 RTA00000624F.c.15.1 M00005565C:A8 898 May 15, 1998 1488 147 RTA00000617F.e.13.2 M00005465C:H2 899 May 15, 1998 1488 148 RTA00000592F.j.06.1 M00006664D:H9 900 May 15, 1998 1488 149 RTA00000615F.n.18.1 M00005359B:G1 901 May 15, 1998 1488 150 RTA00000624F.c.02.1 M00005550B:D9 902 May 15, 1998 1488 151 RTA00000620F.j.10.1 M00006886A:D6 903 May 15, 1998 1488 152 RTA00000620F.e.07.1 M00006860B:H1 904 May 15, 1998 1488 153 RTA00000625F.g.07.1 M00005798B:C11 905 May 15, 1998 1488 154 RTA00000617F.d.22.1 M00005462C:B2 906 May 15, 1998 1488 155 RTA00000622F.a.12.1 M00007006D:D4 907 May 15, 1998 1488 156 RTA00000620F.i.11.1 M00006879D:A10 908 May 15, 1998 1488 157 RTA00000616F.k.03.1 M00005415C:G8 909 May 15, 1998 1488 158 RTA00000624F.k.17.1 M00005636C:D11 910 May 15, 1998 1488 159 RTA00000615F.f.11.1 M00004999B:D12 911 May 15, 1998 1488 160 RTA00000620F.o.07.1 M00006917C:E7 912 May 15, 1998 1488 161 RTA00000617F.k.11.1 M00005493B:C8 913 May 15, 1998 1488 162 RTA00000622F.g.04.1 M00007037B:D4 914 May 15, 1998 1488 163 RTA00000591F.n.04.1 M00005528D:H6 915 May 15, 1998 1488 164 RTA00000625F.a.16.1 M00005706D:A9 916 May 15, 1998 1488 165 RTA00000620F.m.18.1 M00006908C:AS 917 May 15, 1998 1488 166 RTA00000620F.a.04.1 M00006832D:F10 918 May 15, 1998 1488 167 RTA00000624F.j.20.1 M00005632C:D6 919 May 15, 1998 1488 168 RTA00000590F.n.19.1 M00005378C:A10 920 May 15, 1998 1488 169 RTA00000626F.c.13.1 M00006636D:F11 921 May 15, 1998 1488 170 RTA00000617F.f.01.2 M00005468B:D4 922 May 15, 1998 1488 171 RTA00000621F.i.18.2 M00006966C:B7 923 May 15, 1998 1488 172 RTA00000617F.a.13.1 M00005450A:A2 924 May 15, 1998 1488 173 RTA00000591F.m.06.1 M00005513A:D8 925 May 15, 1998 1488 174 RTA00000615F.g.07.1 M00005004B:C11 926 May 15, 1998 1488 175 RTA00000616F.o.24.1 M00005442D:C5 927 May 15, 1998 1488 176 RTA00000617F.a.20.1 M00005451A:E3 928 May 15, 1998 1488 177 RTA00000626F.a.18.1 M00006629D:D4 929 May 15, 1998 1488 178 RTA00000616F.c.23.1 M00005385C:D8 930 May 15, 1998 1488 179 RTA00000623F.m.07.1 M00007193D:A4 931 May 15, 1998 1488 180 RTA00000620F.h.18.1 M00006875D:D10 932 May 15, 1998 1488 181 RTA00000615F.l.16.1 M00005352B:D2 933 May 15, 1998 1488 182 RTA00000592F.c.17.1 M00005708D:B3 934 May 15, 1998 1488 183 RTA00000616F.c.24.1 M00005385C:G5 935 May 15, 1998 1488 184 RTA00000619F.l.16.1 M00006813A:C4 936 May 15, 1998 1488 185 RTA00000622F.c.18.1 M00007015C:G5 937 May 15, 1998 1488 186 RTA00000620F.p.09.1 M00006921B:E3 938 May 15, 1998 1488 187 RTA00000626F.f.08.1 M00006650A:B11 939 May 15, 1998 1488 188 RTA00000621F.h.08.1 M00006960A:G11 940 May 15, 1998 1488 189 RTA00000591F.g.19.1 M00005466A:F12 941 May 15, 1998 1488 190 RTA00000623F.m.10.1 M00007195B:B2 942 May 15, 1998 1488 191 RTA00000619F.j.13.1 M00006796A:H10 943 May 15, 1998 1488 192 RTA00000619F.f.22.1 M00006771A:H7 944 May 15, 1998 1488 193 RTA00000622F.m.06.1 M00007075C:D8 945 May 15, 1998 1488 194 RTA00000623F.i.03.1 M00007154A:E4 946 May 15, 1998 1488 195 RTA00000625F.k.08.1 M00006581D:H8 947 May 15, 1998 1488 196 RTA00000615F.c.13.1 M00004854A:C9 948 May 15, 1998 1488 197 RTA00000619F.j.11.1 M00006796A:C3 949 May 15, 1998 1488 198 RTA00000619F.o.01.1 M00006822D:F7 950 May 15, 1998 1488 199 RTA00000590F.h.12.2 M00004826A:E9 951 May 15, 1998 1488 200 RTA00000623F.d.07.1 M00007121C:H1 952 May 15, 1998 1488 201 RTA00000616F.f.24.1 M00005397C:B3 953 May 15, 1998 1488 202 RTA00000625F.o.03.1 M00006609A:G10 954 May 15, 1998 1488 203 RTA00000619F.k.20.1 M00006807D:D8 955 May 15, 1998 1488 204 RTA00000625F.n.22.1 M00006607B:F4 956 May 15, 1998 1488 205 RTA00000625F.n.03.1 M00006601D:F4 957 May 15, 1998 1488 206 RTA00000619F.c.13.1 M00006756B:B8 958 May 15, 1998 1488 207 RTA00000625F.g.21.1 M00005805D:E6 959 May 15, 1998 1488 208 RTA00000620F.g.06.1 M00006868D:E2 960 May 15, 1998 1488 209 RTA00000622F.l.04.1 M00007065B:B12 961 May 15, 1998 1488 210 RTA00000624F.d.21.1 M00005587B:H2 962 May 15, 1998 1488 211 RTA00000622F.f.20.1 M00007036A:D2 963 May 15, 1998 1488 212 RTA00000616F.d.09.1 M00005388A:F7 964 May 15, 1998 1488 213 RTA00000620F.n.05.1 M00006912B:E1 965 May 15, 1998 1488 214 RTA00000624F.k.22.1 M00005637B:D12 966 May 15, 1998 1488 215 RTA00000618F.p.11.1 M00006739B:B12 967 May 15, 1998 1488 216 RTA00000615F.g.09.1 M00005005C:E6 968 May 15, 1998 1488 217 RTA00000618F.j.23.1 M00006712B:H10 969 May 15, 1998 1488 218 RTA00000617F.l.02.1 M00005497B:H7 970 May 15, 1998 1488 219 RTA00000617F.l.09.1 M00005498B:F8 971 May 15, 1998 1488 220 RTA00000625F.n.21.1 M00006607B:E3 972 May 15, 1998 1488 221 RTA00000623F.c.20.1 M00007118B:B4 973 May 15, 1998 1488 222 RTA00000603F.d.13.1 M00007019A:B1 974 May 15, 1998 1488 223 RTA00000625F.k.06.1 M00006581C:D2 975 May 15, 1998 1488 224 RTA00000624F.b.23.1 M00005548B:E3 976 May 15, 1998 1488 225 RTA00000626F.d.11.1 M00006640D:H8 977 May 15, 1998 1488 226 RTA00000620F.g.14.1 M00006870C:H6 978 May 15, 1998 1488 227 RTA00000621F.l.17.1 M00006980A:F2 979 May 15, 1998 1488 228 RTA00000624F.o.13.1 M00005685A:A4 980 May 15, 1998 1488 229 RTA00000621F.k.18.1 M00006974B:F6 981 May 15, 1998 1488 230 RTA00000591F.a.23.1 M00005411D:A3 982 May 15, 1998 1488 231 RTA00000592F.i.01.1 M00006641C:H2 983 May 15, 1998 1488 232 RTA00000625F.p.10.1 M00006619B:C11 984 May 15, 1998 1488 233 RTA00000622F.h.04.1 M00007041B:C5 985 May 15, 1998 1488 234 RTA00000591F.e.08.1 M00005446A:G1 986 May 15, 1998 1488 235 RTA00000619F.d.13.1 M00006758D:C4 987 May 15, 1998 1488 236 RTA00000622F.p.10.1 M00007099A:F9 988 May 15, 1998 1488 237 RTA00000623F.m.04.1 M00007192C:H8 989 May 15, 1998 1488 238 RTA00000617F.i.06.1 M00005483A:F5 990 May 15, 1998 1488 239 RTA00000624F.d.24.1 M00005589C:B3 991 May 15, 1998 1488 240 RTA00000616F.p.08.1 M00005444B:E11 992 May 15, 1998 1488 241 RTA00000615F.j.18.1 M00005326B:F3 993 May 15, 1998 1488 242 RTA00000625F.p.19.1 M00006621A:G10 994 May 15, 1998 1488 243 RTA00000624F.h.09.1 M00005620C:C5 995 May 15, 1998 1488 244 RTA00000619F.d.23.1 M00006760D:G12 996 May 15, 1998 1488 245 RTA00000618F.f.24.1 M00006692B:E4 997 May 15, 1998 1488 246 RTA00000617F.l.12.1 M00005498C:G5 998 May 15, 1998 1488 247 RTA00000621F.o.09.1 M00006993B:B9 999 May 15, 1998 1488 248 RTA00000616F.p.04.1 M00005443D:C12 1000 May 15, 1998 1488 249 RTA00000620F.c.08.1 M00006841D:A8 1001 May 15, 1998 1488 250 RTA00000625F.n.01.1 M00006601C:A7 1002 May 15, 1998 1488 251 RTA00000617F.k.10.1 M00005493B:A12 1003 May 15, 1998 1488 252 RTA00000624F.l.11.1 M00005641B:E2 1004 May 15, 1998 1488 253 RTA00000624F.h.06.1 M00005619C:H10 1005 May 15, 1998 1488 254 RTA00000624F.h.11.1 M00005621A:G10 1006 May 15, 1998 1488 255 RTA00000590F.h.07.2 M00004824C:G9 1007 May 15, 1998 1488 256 RTA00000590F.o.09.1 M00005384A:A1 1008 May 15, 1998 1488 257 RTA00000620F.e.16.1 M00006863B:E6 1009 May 15, 1998 1488 258 RTA00000620F.k.11.1 M00006893C:B2 1010 May 15, 1998 1488 259 RTA00000619F.o.18.4 M00006825C:D6 1011 May 15, 1998 1488 260 RTA00000621F.k.03.1 M00006972A:F10 1012 May 15, 1998 1488 261 RTA00000625F.c.11.1 M00005722D:G3 1013 May 15, 1998 1488 262 RTA00000618F.n.05.1 M00006727B:G8 1014 May 15, 1998 1488 263 RTA00000623F.d.02.1 M00007119B:H10 1015 May 15, 1998 1488 264 RTA00000615F.k.05.1 M00005330C:F9 1016 May 15, 1998 1488 265 RTA00000623F.f.09.1 M00007132D:G8 1017 May 15, 1998 1488 266 RTA00000622F.d.01.1 M00007016C:E6 1018 May 15, 1998 1488 267 RTA00000618F.p.10.1 M00006739B:B10 1019 May 15, 1998 1488 268 RTA00000624F.l.23.1 M00005645D:F8 1020 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285 RTA00000619F.n.23.4 M00006822D:D5 1037 May 15, 1998 1488 286 RTA00000616F.k.16.1 M00005417A:E10 1038 May 15, 1998 1488 287 RTA00000625F.f.21.1 M00005783A:C5 1039 May 15, 1998 1488 288 RTA00000619F.b.17.1 M00006751B:B11 1040 May 15, 1998 1488 289 RTA00000622F.h.11.1 M00007042A:E7 1041 May 15, 1998 1488 290 RTA00000621F.k.12.1 M00006973D:E11 1042 May 15, 1998 1488 291 RTA00000620F.p.08.1 M00006921B:E1 1043 May 15, 1998 1488 292 RTA00000625F.d.13.1 M00005762D:A1 1044 May 15, 1998 1488 293 RTA00000592F.g.18.1 M00006618C:G8 1045 May 15, 1998 1488 294 RTA00000622F.b.17.1 M00007012B:D7 1046 May 15, 1998 1488 295 RTA00000624F.i.07.1 M00005625D:C3 1047 May 15, 1998 1488 296 RTA00000619F.c.01.1 M00006754B:D5 1048 May 15, 1998 1488 297 RTA00000621F.a.07.1 M00006926A:H11 1049 May 15, 1998 1488 298 RTA00000620F.d.21.1 M00006855C:H2 1050 May 15, 1998 1488 299 RTA00000616F.c.15.1 M00005383D:E7 1051 May 15, 1998 1488 300 RTA00000619F.n.19.4 M00006822A:D7 1052 May 15, 1998 1488 301 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May 15, 1998 1488 497 RTA00000624F.a.17.1 M00005535B:F6 1249 May 15, 1998 1488 498 RTA00000621F.n.17.1 M00006990D:D6 1250 May 15, 1998 1488 499 RTA00000625F.n.02.1 M00006601C:E6 1251 May 15, 1998 1488 500 RTA00000591F.n.05.1 M00005530B:E4 1252 May 15, 1998 1488 501 RTA00000622F.n.09.1 M00007084B:A5 1253 May 15, 1998 1488 502 RTA00000617F.l.05.1 M00005497C:C10 1254 May 15, 1998 1488 503 RTA00000623F.j.08.2 M00007163A:B10 1255 May 15, 1998 1488 504 RTA00000626F.g.02.1 M00006656C:C10 1256 May 15, 1998 1488 505 RTA00000617F.l.06.1 M00005497C:C12 1257 May 15, 1998 1488 506 RTA00000592F.a.06.1 M00005635B:A6 1258 May 15, 1998 1488 507 RTA00000591F.j.11.1 M00005485C:A3 1259 May 15, 1998 1488 508 RTA00000622F.h.21.1 M00007046A:D2 1260 May 15, 1998 1488 509 RTA00000591F.h.03.1 M00005468D:F4 1261 May 15, 1998 1488 510 RTA00000620F.g.22.1 M00006872B:G1 1262 May 15, 1998 1488 511 RTA00000617F.c.05.1 M00005456B:E3 1263 May 15, 1998 1488 512 RTA00000616F.e.15.3 M00005393A:E11 1264 May 15, 1998 1488 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May 15, 1998 1489 234 RTA00000633F.p.04.1 M00022902D:D3 1511 May 15, 1998 1489 235 RTA00000633F.n.08.1 M00022856A:D2 1512 May 15, 1998 1489 236 RTA00000628F.h.06.1 M00021897B:A6 1513 May 15, 1998 1489 237 RTA00000628F.d.05.1 M00021841C:D7 1514 May 15, 1998 1489 238 RTA00000627F.l.22.1 M00021624B:A3 1515 May 15, 1998 1489 239 RTA00000630F.f.19.1 M00022212C:C2 1516 May 15, 1998 1489 240 RTA00000630F.h.17.1 M00022220C:F8 1517 May 15, 1998 1489 241 RTA00000632F.i.15.1 M00022583B:E5 1518 May 15, 1998 1489 242 RTA00000633F.j.15.1 M00022745B:G2 1519 May 15, 1998 1489 243 RTA00000628F.k.05.1 M00021932C:G10 1520 May 15, 1998 1489 244 RTA00000633F.d.04.1 M00022685A:F11 1521 May 15, 1998 1489 245 RTA00000639F.h.10.1 M00023094A:C4 1522 May 15, 1998 1489 246 RTA00000632F.f.11.1 M00022535D:C4 1523 May 15, 1998 1489 247 RTA00000631F.p.20.1 M00022480B:E7 1524 May 15, 1998 1489 248 RTA00000629F.o.17.2 M00022150A:H6 1525 May 15, 1998 1489 249 RTA00000592F.l.23.1 M00007986C:C5 1526 May 15, 1998 1489 250 RTA00000630F.d.10.1 M00022189A:A1 1527 May 15, 1998 1489 251 RTA00000632F.j.19.1 M00022600C:A6 1528 May 15, 1998 1489 252 RTA00000633F.n.10.1 M00022856B:F4 1529 May 15, 1998 1489 253 RTA00000628F.h.13.1 M00021905A:G5 1530 May 15, 1998 1489 254 RTA00000633F.k.05.1 M00022763A:E10 1531 May 15, 1998 1489 255 RTA00000633F.i.11.1 M00022735B:B1 1532 May 15, 1998 1489 256 RTA00000633F.o.20.1 M00022900D:G3 1533 May 15, 1998 1489 257 RTA00000628F.b.19.1 M00021690D:E5 1534 May 15, 1998 1489 258 RTA00000627F.p.14.1 M00021667D:E3 1535 May 15, 1998 1489 259 RTA00000628F.n.15.1 M00021983B:B3 1536 May 15, 1998 1489 260 RTA00000592F.p.22.1 M00008074D:C1 1537 May 15, 1998 1489 261 RTA00000628F.m.19.1 M00021977D:E2 1538 May 15, 1998 1489 262 RTA00000593F.a.05.1 M00008078C:C6 1539 May 15, 1998 1489 263 RTA00000639F.g.17.1 M00023036D:C4 1540 May 15, 1998 1489 264 RTA00000632F.j.15.1 M00022599A:C3 1541 May 15, 1998 1489 265 RTA00000592F.l.04.1 M00007971A:B4 1542 May 15, 1998 1489 266 RTA00000629F.c.07.1 M00022054D:C5 1543 May 15, 1998 1489 267 RTA00000592F.l.21.1 M00007985A:B9 1544 May 15, 1998 1489 268 RTA00000629F.h.15.1 M00022085C:A7 1545 May 15, 1998 1489 269 RTA00000633F.n.02.1 M00022835C:E6 1546 May 15, 1998 1489 270 RTA00000630F.n.24.1 M00022278D:F10 1547 May 15, 1998 1489 271 RTA00000592F.k.09.1 M00007953B:B3 1548 May 15, 1998 1489 272 RTA00000592F.l.10.1 M00007974B:C11 1549 May 15, 1998 1489 273 RTA00000628F.k.04.1 M00021932C:C5 1550 May 15, 1998 1489 274 RTA00000630F.h.24.1 M00022226C:B6 1551 May 15, 1998 1489 275 RTA00000629F.i.13.1 M00022091B:B7 1552 May 15, 1998 1489 276 RTA00000630F.b.01.1 M00022170D:H7 1553 May 15, 1998 1489 277 RTA00000628F.g.13.1 M00021886D:E4 1554 May 15, 1998 1489 278 RTA00000592F.m.13.1 M00007995D:E6 1555 May 15, 1998 1489 279 RTA00000633F.h.20.1 M00022728A:A9 1556 May 15, 1998 1489 280 RTA00000593F.d.08.2 M00021860B:G6 1557 May 15, 1998 1489 281 RTA00000629F.f.01.1 M00022071B:D5 1558 May 15, 1998 1489 282 RTA00000632F.i.11.1 M00022582C:E12 1559 May 15, 1998 1489 283 RTA00000632F.j.24.1 M00022604B:C11 1560 May 15, 1998 1489 284 RTA00000629F.f.03.1 M00022071C:C9 1561 May 15, 1998 1489 285 RTA00000593F.b.04.1 M00008094A:E10 1562 May 15, 1998 1489 286 RTA00000628F.l.12.1 M00021952B:F11 1563 May 15, 1998 1489 287 RTA00000632F.j.12.1 M00022597B:F11 1564 May 15, 1998 1489 288 RTA00000592F.k.23.1 M00007964B:D10 1565 May 15, 1998 1489 289 RTA00000632F.g.07.1 M00022556B:C4

TABLE 1B SEQ ID NO: Sample Name Overlap Clone Name 1566 803.F11.sp6:165002 VO M00004236D:E07 1567 180.B11.sp6:135937 VO M00001453B:F08 1568 1033.D01.sp6:188349 VO M00001455A:E09 1569 1164.H10.sp6:186952 VO M00001455A:E09 1570 80.E12.sp6:130267 VNO 1571 121.C2.sp6:131906 VNO 1572 1035.D01.sp6:188733 VO M00003939A:A02 1573 1034.G03.sp6:188579 VNO 1574 020.C1.sp6:128615 VO M00003820C:A09 1575 019.B1.sp6:128411 VO M00003820C:A09 1576 803.F4.sp6:164995 VO M00004052C:B05 1577 1033.C06.sp6:188342 VO M00001654D:F06 1578 1035.H07.sp6:188787 VO M00004034C:F05 1579 396.C9.sp6:149508 VO M00004034C:F05 1580 396.D9.sp6:149520 VO M00004035B:F05 1581 1035.B08.sp6:188716 VO M00004035B:F05 1582 396.H9.sp6:149568 VNO 1583 1035.D09.sp6:188741 VO M00004037C:D07 1584 1036.B05.sp6:188905 VO M00004115C:H04 1585 404.G2.sp6:162929 VNO 1586 1035.D07.sp6:188739 VO M00004031D:G02 1587 1034.A05.sp6:188509 VO M00003829A:B08 1588 395.B5.sp6:149300 VO M00003829A:B08 1589 1034.F07.sp6:188571 VO M00003852D:D03 1590 1035.E04.sp6:188748 VO M00003982A:G03 1591 396.F3.sp6:149538 VO M00003982A:G03 1592 396.H3.sp6:149562 VO M00003982B:C10 1593 1035.F04.sp6:188760 VNO 1594 396.D4.sp6:149515 VO M00003983A:D02 1595 1035.G04.sp6:188772 VO M00003983A:D02 1596 396.D5.sp6:149516 VO M00003985A:C01 1597 1035.B05.sp6:188713 VO M00003985A:C01 1598 1035.C06.sp6:188726 VO M00004028C:D01 1599 396.A7.sp6:149482 VNO 1600 1035.E06.sp6:188750 VO M00004029C:B03 1601 801.E1.sp6:164692 VO M00001344D:G11 1602 801.F1.sp6:164704 VO M00001345A:A12 1603 801.A2.sp6:164645 VNO 1604 801.B2.sp6:164657 VNO 1605 801.C2.sp6:164669 VO M00001347A:G06 1606 801.D2.sp6:164681 VO M00001347B:H01 1607 801.E2.sp6:164693 VNO 1608 801.F2.sp6:164705 VNO 1609 801.A3.sp6:164646 VO M00001355B:A01 1610 801.B3.sp6:164658 VO M00001358D:D09 1611 801.C3.sp6:164670 VO M00001359A:B07 1612 801.D3.sp6:164682 VO M00001362A:C10 1613 801.E3.sp6:164694 VO M00001362B:A09 1614 801.G3.sp6:164718 VO M00001365D:D12 1615 801.H3.sp6:164730 VO M00001365D:H09 1616 801.A4.sp6:164647 VNO 1617 801.B4.sp6:164659 VO M00001370A:G09 1618 801.C4.sp6:164671 VO M00001370B:B04 1619 801.D4.sp6:164683 VO M00001370B:B12 1620 801.E4.sp6:164695 VNO 1621 801.G4.sp6:164719 VO M00001374D:D09 1622 801.D5.sp6:164684 VO M00001377C:B08 1623 801.F5.sp6:164708 VNO 1624 801.G5.sp6:164720 VNO 1625 801.H5.sp6:164732 VNO 1626 801.A6.sp6:164649 VO M00001384A:C09 1627 801.B6.sp6:164661 VO M00001387A:A04 1628 801.D6.sp6:164685 VO M00001389B:B06 1629 801.E6.sp6:164697 VO M00001390A:C06 1630 801.F6.sp6:164709 VO M00001390A:H01 1631 801.D7.sp6:164686 VNO 1632 801.E7.sp6:164698 VO M00001399C:E10 1633 1033.A01.sp6:188313 VO M00001399D:F09 1634 801.G7.sp6:164722 VNO 1635 801.H7.sp6:164734 VO M00001401D:D04 1636 801.A8.sp6:164651 VNO 1637 801.B8.sp6:164663 VO M00001402D:C07 1638 801.C8.sp6:164675 VO M00001402D:H03 1639 801.D8.sp6:164687 VO M00001403B:A01 1640 801.E8.sp6:164699 VO M00001405D:F05 1641 801.G8.sp6:164723 VO M00001406C:A11 1642 801.B9.sp6:164664 VO M00001407B:A08 1643 801.C9.sp6:164676 VO M00001407D:H11 1644 801.D9.sp6:164688 VNO 1645 801.E9.sp6:164700 VNO 1646 801.F9.sp6:164712 VO M00001411A:D01 1647 801.G9.sp6:164724 VNO 1648 801.H9.sp6:164736 VO M00001411C:G02 1649 801.B10.sp6:164665 VO M00001412A:A11 1650 801.C10.sp6:164677 VNO 1651 801.D10.sp6:164689 VNO 1652 801.E10.sp6:164701 VO M00001415D:E12 1653 801.F10.sp6:164713 VNO 1654 801.G10.sp6:164725 VO M00001417B:E01 1655 020.A6.sp6:128596 VO M00001417B:E01 1656 801.H10.sp6:164737 VNO 1657 801.A11.sp6:164654 VO M00001417C:E02 1658 801.B11.sp6:164666 VNO 1659 801.C11.sp6:164678 VO M00001421A:H07 1660 801.F11.sp6:164714 VO M00001423C:D06 1661 801.G11.sp6:164726 VO M00001424A:H09 1662 801.H11.sp6:164738 VO M00001425C:E10 1663 801.B12.sp6:164667 VO M00001426A:F09 1664 801.C12.sp6:164679 VO M00001426D:D09 1665 801.E12.sp6:164703 VO M00001431A:C10 1666 801.F12.sp6:164715 VO M00001431A:E05 1667 801.G12.sp6:164727 VO M00001432A:F12 1668 801.H12.sp6:164739 VO M00001432B:H08 1669 802.A1.sp6:164740 VO M00001432C:G01 1670 802.B1.sp6:164752 VO M00001433A:C07 1671 802.C1.sp6:164764 VNO 1672 802.D1.sp6:164776 VO M00001434A:A01 1673 802.E1.sp6:164788 VNO 1674 802.F1.sp6:164800 VO M00001435A:F03 1675 802.G1.sp6:164812 VO M00001435A:G01 1676 802.H1.sp6:164824 VO M00001435B:G10 1677 802.A2.sp6:164741 VO M00001435C:G08 1678 802.B2.sp6:164753 VNO 1679 802.C2.sp6:164765 VO M00001435D:A06 1680 802.D2.sp6:164777 VO M00001436D:C10 1681 802.E2.sp6:164789 VO M00001437B:B05 1682 802.G2.sp6:164813 VNO 1683 802.H2.sp6:164825 VO M00001438C:H05 1684 802.A3.sp6:164742 VNO 1685 802.B3.sp6:164754 VO M00001439B:F10 1686 802.C3.sp6:164766 VO M00001439C:A01 1687 802.D3.sp6:164778 VO M00001439C:G06 1688 802.E3.sp6:164790 VO M00001441D:H05 1689 802.F3.sp6:164802 VO M00001442A:D08 1690 802.G3.sp6:164814 VNO 1691 802.H3.sp6:164826 VO M00001443D:A01 1692 802.A4.sp6:164743 VNO 1693 802.B4.sp6:164755 VO M00001444A:A09 1694 802.C4.sp6:164767 VNO 1695 802.D4.sp6:164779 VNO 1696 802.E4.sp6:164791 VO M00001446D:B10 1697 1033.B01.sp6:188325 VO M00001448A:D05 1698 802.F4.sp6:164803 VO M00001451B:H11 1699 802.G4.sp6:164815 VNO 1700 802.H4.sp6:164827 VO M00001452B:H06 1701 802.A5.sp6:164744 VO M00001452D:E05 1702 802.C5.sp6:164768 VO M00001453D:F09 1703 1033.C01.sp6:188337 VO M00001455A:C03 1704 1033.E01.sp6:188361 VO M00001456C:F02 1705 1033.F01.sp6:188373 VO M00001458B:F06 1706 802.D5.sp6:164780 VO M00001463C:A01 1707 802.E5.sp6:164792 VO M00001466C:F02 1708 802.F5.sp6:164804 VNO 1709 802.G5.sp6:164816 VO M00001471C:G03 1710 1033.G01.sp6:188385 VO M00001478A:B06 1711 1033.H01.sp6:188397 VO M00001487D:G03 1712 802.H5.sp6:164828 VO M00001488B:G12 1713 802.B6.sp6:164757 VO M00001489B:F08 1714 802.C6.sp6:164769 VO M00001489D:C08 1715 802.D6.sp6:164781 VO M00001490B:G04 1716 802.E6.sp6:164793 VO M00001491C:C01 1717 802.F6.sp6:164805 VNO 1718 802.G6.sp6:164817 VO M00001496A:B03 1719 802.H6.sp6:164829 VNO 1720 802.A7.sp6:164746 VO M00001496D:D02 1721 802.B7.sp6:164758 VNO 1722 802.D7.sp6:164782 VNO 1723 802.E7.sp6:164794 VO M00001500A:D09 1724 802.F7.sp6:164806 VNO 1725 802.G7.sp6:164818 VNO 1726 802.H7.sp6:164830 VO M00001504D:D09 1727 802.A8.sp6:164747 VO M00001505A:E09 1728 802.B8.sp6:164759 VO M00001506A:F01 1729 802.D8.sp6:164783 VO M00001517D:C03 1730 802.E8.sp6:164795 VO M00001518D:A10 1731 1033.A02.sp6:188314 VO M00001530A:D11 1732 802.F8.sp6:164807 VO M00001536B:B11 1733 802.G8.sp6:164819 VO M00001537B:C12 1734 1033.B02.sp6:188326 VO M00001539B:B01 1735 802.H8.sp6:164831 VO M00001542C:D10 1736 802.A9.sp6:164748 VO M00001542C:F06 1737 802.B9.sp6:164760 VNO 1738 802.C9.sp6:164772 VO M00001543A:E04 1739 802.E9.sp6:164796 VO M00001546B:H01 1740 802.G9.sp6:164820 VO M00001551D:C12 1741 802.H9.sp6:164832 VO M00001552B:D01 1742 802.A10.sp6:164749 VO M00001553D:B06 1743 802.B10.sp6:164761 VNO 1744 802.C10.sp6:164773 VO M00001556D:A11 1745 802.D10.sp6:164785 VNO 1746 802.E10.sp6:164797 VO M00001557C:B08 1747 802.F10.sp6:164809 VO M00001558B:A12 1748 802.G10.sp6:164821 VO M00001560C:C01 1749 802.H10.sp6:164833 VO M00001561B:C10 1750 1033.C02.sp6:188338 VO M00001563C:D06 1751 1033.D02.sp6:188350 VO M00001564C:D04 1752 1033.E02.sp6:188362 VO M00001565A:A02 1753 1033.F02.sp6:188374 VO M00001569B:F04 1754 1033.G02.sp6:188386 VO M00001572C:E07 1755 1033.H02.sp6:188398 VO M00001575A:H02 1756 1033.A03.sp6:188315 VO M00001582D:B10 1757 1033.B03.sp6:188327 VO M00001584C:A03 1758 1033.E04.sp6:188364 VO M00001618B:F02 1759 1033.B08.sp6:188332 VO M00001687C:A06 1760 1033.H12.sp6:188408 VNO 1761 1034.C05.sp6:188533 VO M00003830A:A10 1762 1034.F05.sp6:188569 VO M00003833D:D06 1763 1034.D06.sp6:188546 VO M00003839D:G06 1764 1034.G06.sp6:188582 VO M00003843A:B01 1765 1034.H07.sp6:188595 VO M00003858A:D01 1766 1034.A08.sp6:188512 VO M00003859C:B09 1767 1034.E08.sp6:188560 VO M00003868D:F07 1768 1034.C10.sp6:188538 VO M00003895D:A03 1769 1034.B11.sp6:188527 VO M00003906C:H12 1770 1034.G11.sp6:188587 VNO 1771 1034.D12.sp6:188552 VO M00003918C:E07 1772 1035.H01.sp6:188781 VNO 1773 1035.G02.sp6:188770 VNO 1774 325.D3.sp6:145862 VNO 1775 1035.A05.sp6:188701 VNO 1776 1035.F05.sp6:188761 VNO 1777 803.H1.sp6:165016 VNO 1778 803.F2.sp6:164993 VNO 1779 1035.G06.sp6:188774 VO M00004030A:G12 1780 1035.A07.sp6:188703 VO M00004030B:C05 1781 1035.B07.sp6:188715 VNO 1782 1035.D08.sp6:188740 VO M00004035D:C05 1783 1035.G08.sp6:188776 VO M00004036C:D01 1784 1035.A09.sp6:188705 VNO 1785 1035.B09.sp6:188717 VO M00004037B:B05 1786 1035.G09.sp6:188777 VO M00004038C:D12 1787 803.C4.sp6:164959 VO M00004051C:D02 1788 803.A5.sp6:164936 VNO 1789 774.E2.sp6:162484 VO M00004054D:D02 1790 803.D5.sp6:164972 VNO 1791 803.C6.sp6:164961 VNO 1792 803.D6.sp6:164973 VNO 1793 1035.A12.sp6:188708 VNO 1794 1035.C12.sp6:188732 VO M00004076D:B03 1795 774.E4.sp6:162500 VO M00004081B:C11 1796 1035.G12.sp6:188780 VO M00004081B:C11 1797 1036.H01.sp6:188973 VO M00004089A:F02 1798 1036.D02.sp6:188926 VO M00004091B:G04 1799 1036.G03.sp6.188963 VO M00004103B:C07 1800 1036.F04.sp6:188952 VNO 1801 1036.H04.sp6:188976 VO M00004115A:F01 1802 1036.A05.sp6:188893 VO M00004115A:G09 1803 1036.B06.sp6:188906 VNO 1804 803.A7.sp6:164938 VNO 1805 803.E8.sp6:164987 VNO 1806 803.F8.sp6:164999 VO M00004159D:C04 1807 803.A9.sp6:164940 VO M00004160A:D07 1808 1036.D06.sp6:188930 VO M00004178B:F06 1809 1036.F06.sp6:188954 VNO 1810 1036.H06.sp6:188978 VO M00004184B:F11 1811 1036.D09.sp6:188933 VO M00004202B:A02 1812 1036.F09.sp6:188957 VO M00004202B:G09 1813 803.H10.sp6:165025 VNO 1814 803.H11.sp6:165026 VNO 1815 803.C12.sp6:164967 VNO 1816 804.D1.sp6:165160 VNO 1817 983.D01.sp6:186199 VO M00004247B:C11 1818 1036.D11.sp6:188935 VO M00004249C:E12 1819 804.B3.sp6:165138 VNO 1820 983.B03.sp6:186181 VO M00004277D:C08 1821 804.F5.sp6:165188 VNO 1822 983.F05.sp6:186221 VO M00004337D:G08 1823 983.G05.sp6:186230 VO M00004345A:H06 1824 804.G5.sp6:165200 VNO 1825 983.A06.sp6:186174 VO M00004350B:F06 1826 804.A6.sp6:165129 VNO 1827 774.D12.sp6:162563 VO M00004350B:F06 1828 804.F7.sp6:165190 VNO 1829 983.F07.sp6:186223 VO M00004446A:G01 1830 992.E01.sp6:186367 VO M00005332A:H10 1831 992.G02.sp6:186392 VNO 1832 992.A04.sp6:186322 VO M00005378C:A10 1833 992.D04.sp6:186358 VO M00005384A:A01 1834 992.B05.sp6:186335 VO M00005390B:G10 1835 992.H05.sp6:186407 VO M00005399A:D01 1836 992.A06.sp6:186324 VNO 1837 992.B06.sp6:186336 VO M00005399D:B02 1838 020.G4.sp6:128666 VO M00005404C:F02 1839 020.G8.sp6:128670 VO M00005411A:C07 1840 992.H06.sp6:186408 VNO 1841 953.F01.sp6:185185 VO M00005411D:A03 1842 992.A07.sp6:186325 VO M00005411D:A03 1843 992.D08.sp6:186362 VO M00005446A:G01 1844 992.B09.sp6:186339 VO M00005450B:B01 1845 953.A07.sp6:185131 VO M00005450B:B01 1846 953.E07.sp6:185179 VO M00005452C:A02 1847 992.E09.sp6:186375 VO M00005452C:A02 1848 992.G09.sp6:186399 VO M00005455A:D01 1849 992.H09.sp6:186411 VO M00005455A:G03 1850 992.D11.sp6:186365 VNO 1851 953.H10.sp6:185218 VO M00005477C:D08 1852 992.F11.sp6:186389 VO M00005477C:D08 1853 953.D11.sp6:185171 VO M00005480A:H12 1854 992.H11.sp6:186413 VO M00005480C:B12 1855 992.A12.sp6:186330 VO M00005481C:A05 1856 953.E11.sp6:185183 VO M00005481C:A05 1857 953.C12.sp6:185160 VO M00005485C:A03 1858 992.F12.sp6:186390 VO M00005485C:A03 1859 953.E12.sp6:185184 VO M00005486C:B03 1860 993.C03.sp6:186537 VO M00005510B:D06 1861 993.D03.sp6:186549 VO M00005513A:D08 1862 993.E03.sp6:186561 VO M00005524C:B01 1863 993.G03.sp6:186585 VO M00005528D:H06 1864 993.A04.sp6:186514 VO M00005530B:E04 1865 993.B05.sp6:186527 VO M00005616B:D05 1866 993.C06.sp6:186540 VNO 1867 993.B08.sp6:186530 VO M00005704A:B11 1868 993.C08.sp6:186542 VO M00005708D:B03 1869 993.D09.sp6:186555 VO M00005765C:C04 1870 993.E09.sp6:186567 VO M00005772A:F03 1871 993.F10.sp6:186580 VO M00006577B:H12 1872 993.C11.sp6:186545 VO M00006587A:H08 1873 993.D11.sp6:186557 VNO 1874 993.G11.sp6:186593 VNO 1875 993.H12.sp6:186606 VO M00006615B:F05 1876 626.B2.sp6:157417 VO M00007953B:B03 1877 627.E6.sp6:157649 VO M00007985A:B09 1878 633.C4.sp6:156098 VO M00008061A:F02 1879 636.F10.sp6:158241 VO M00022070B:C10 1880 641.G8.GZ42:158428 VO M00022109B:A11 1881 642.B7.sp6:156281 VO M00022176C:A08 1882 1010.F02.sp6:189986 VNO 1883 1010.A09.sp6:189945 VO M00022828C:E04 1884 1033.C03.sp6:188339 VO M0000 1586A:F09 1885 1033.D03.sp6:188351 VO M00001588D:H08 1886 1033.E03.sp6:188363 VO M00001589C:D12 1887 1033.F03.sp6:188375 VO M00001589D:G10 1888 1033.G03.sp6:188387 VO M00001590D:A07 1889 802.A11.sp6:164750 VNO 1890 802.B11.sp6:164762 VO M00001597C:B03 1891 1033.H03.sp6:188399 VO M00001598C:D10 1892 1033.A04.sp6:188316 VO M00001599A:H09 1893 1033.B04.sp6:188328 VNO 1894 1033.C04.sp6:188340 VO M00001610B:A01 1895 1033.D04.sp6:188352 VO M00001614C:G04 1896 1033.F04.sp6:188376 VO M00001618C:E06 1897 1033.G04.sp6:188388 VO M00001621C:A04 1898 802.E11.sp6:164798 VNO 1899 802.G11.sp6:164822 VO M00001623B:B01 1900 802.H11.sp6:164834 VO M00001623D:A09 1901 1033.H04.sp6:188400 VO M00001626B:H05 1902 1033.A05.sp6:188317 VNO 1903 1033.B05.sp6:188329 VO M00001634C:E12 1904 1033.C05.sp6:188341 VO M00001639A:A04 1905 1033.D05.sp6:188353 VNO 1906 1033.E05.sp6:188365 VO M00001640A:F04 1907 1033.F05.sp6:188377 VO M00001641B:G05 1908 802.C12.sp6:164775 VO M00001644D:F09 1909 1033.G05.sp6:188389 VO M00001647C:C07 1910 1033.H05.sp6:188401 VO M00001648C:F06 1911 1033.A06.sp6:188318 VNO 1912 1033.B06.sp6:188330 VO M00001649D:H05 1913 1033.D06.sp6:188354 VO M00001655A:F07 1914 1033.E06.sp6:188366 VO M00001656D:F11 1915 1033.F06.sp6:188378 VNO 1916 1033.G06.sp6:188390 VNO 1917 1033.H06.sp6:188402 VO M00001660A:F10 1918 1033.A07.sp6:188319 VO M00001663C:C03 1919 1033.B07.sp6:188331 VO M00001669A:H11 1920 1033.C07.sp6:188343 VO M00001669B:A03 1921 1033.D07.sp6:188355 VO M00001675C:B03 1922 1033.E07.sp6:188367 VO M00001677A:A06 1923 1033.F07.sp6:188379 VO M00001677A:A12 1924 1033.G07.sp6:188391 VO M00001678D:A12 1925 1033.H07.sp6:188403 VNO 1926 1033.A08.sp6:188320 VNO 1927 1033.C08.sp6:188344 VO M00001693D:F07 1928 1033.D08.sp6:188356 VO M00003741A:E01 1929 1033.E08.sp6:188368 VO M00003745C:E03 1930 1033.F08.sp6:188380 VO M00003746A:E01 1931 1033.G08.sp6:188392 VNO 1932 1033.H08.sp6:188404 VO M00003748B:B06 1933 1033.A09.sp6:188321 VO M00003749B:C08 1934 1033.B09.sp6:188333 VO M00003749D:G07 1935 1033.C09.sp6:188345 VO M00003752A:B06 1936 1033.D09.sp6:188357 VO M00003752D:D09 1937 1033.E09.sp6:188369 VO M00003753C:B01 1938 1033.F09.sp6:188381 VO M00003754C:F01 1939 1033.G09.sp6:188393 VO M00003756C:C08 1940 1033.H09.sp6:188405 VO M00003759A:E10 1941 1033.A10.sp6:188322 VO M00003762A:D11 1942 1033.B10.sp6:188334 VO M00003763B:D03 1943 1033.C10.sp6:188346 VO M00003763D:F06 1944 1033.D10.sp6:188358 VO M00003765D:E02 1945 1033.E10.sp6:188370 VO M00003766A:G09 1946 1033.F10.sp6:188382 VO M00003766B:G04 1947 1033.G10.sp6:188394 VO M00003767C:F04 1948 1033.H10.sp6:188406 VO M00003769B:A04 1949 1033.A11.sp6:188323 VO M00003769D:G12 1950 1033.B11.sp6:188335 VO M00003770D:C07 1951 1033.C11.sp6:188347 VO M00003771A:G09 1952 1033.D11.sp6:188359 VO M00003771D:A10 1953 1033.E11.sp6:188371 VO M00003773A:C09 1954 1033.F11.sp6:188383 VO M00003773B:E09 1955 1033.G11.sp6:188395 VO M00003773B:G08 1956 1033.H11.sp6:188407 VO M00003773C:G06 1957 1033.A12.sp6:188324 VO M00003773D:C02 1958 802.E12.sp6:164799 VNO 1959 802.F12.sp6:164811 VNO 1960 802.G12.sp6:164823 VO M00003784C:B09 1961 802.H12.sp6.164835 VO M00003785D:E01 1962 803.A1.sp6:164932 VNO 1963 803.B1.sp6:164944 VNO 1964 803.C1.sp6:164956 VNO 1965 1033.B12.sp6:188336 VO M00003789C:E03 1966 1033.C12.sp6:188348 VO M00003790B:F12 1967 1033.D12.sp6:188360 VO M00003793C:D11 1968 1033.F12.sp6:188384 VO M00003796B:C07 1969 1033.G12.sp6:188396 VO M00003796C:H03 1970 1034.A01.sp6:188505 VO M00003797D:H06 1971 1034.B01.sp6:188517 VNO 1972 1034.C01.sp6:188529 VO M00003801D:F05 1973 1034.D01.sp6:188541 VO M00003805A:G05 1974 1034.E01.sp6:188553 VO M00003808C:D09 1975 1034.F01.sp6:188565 VO M00003809A:A12 1976 1034.G01.sp6:188577 VO M00003809A:H12 1977 1034.H01.sp6:188589 VO M00003809B:D08 1978 1034.A02.sp6:188506 VO M00003811B:E07 1979 1034.B02.sp6:188518 VO M00003812B:F08 1980 1034.C02.sp6:188530 VO M00003812D:E08 1981 1034.D02.sp6:188542 VO M00003813D:A06 1982 1034.E02.sp6:188554 VO M00003815C:A06 1983 1034.F02.sp6:188566 VNO 1984 1034.G02.sp6:188578 VNO 1985 1034.H02.sp6:188590 VO M00003818A:F09 1986 1034.A03.sp6:188507 VO M00003818B:A01 1987 1034.B03.sp6:188519 VO M00003818C:E09 1988 1034.C03.sp6:188531 VNO 1989 1034.D03.sp6:188543 VO M00003819C:E04 1990 1034.E03.sp6:188555 VO M00003819D:G09 1991 1034.F03.sp6:188567 VO M00003820A:H04 1992 1034.H03.sp6:188591 VO M00003820D:E02 1993 1034.A04.sp6:188508 VO M00003821C:E04 1994 1034.B04.sp6:188520 VO M00003822A:G05 1995 803.E12.sp6:164991 VNO 1996 020.E2.sp6:128640 VO M00004242C:C01 1997 019.F9.sp6:128467 VO M00006720C:C11 1998 019.G10.sp6:128480 VO M00007019A:B01 1999 1034.C04.sp6:188532 VNO 2000 1034.D04.sp6:188544 VO M00003825B:A05 2001 1034.E04.sp6:188556 VNO 2002 1034.F04.sp6:188568 VO M00003825C:B02 2003 1034.G04.sp6:188580 VO M00003825C:B12 2004 1034.B05.sp6:188521 VO M00003829A:E02 2005 1034.D05.sp6:188545 VO M00003832B:G03 2006 1034.E05.sp6:188557 VO M00003833B:A11 2007 1034.G05.sp6:188581 VO M00003834A:A03 2008 1034.A06.sp6:188510 VO M00003835D:H05 2009 1034.B06.sp6:188522 VO M00003837C:F05 2010 1034.C06.sp6:188534 VNO 2011 1034.E06.sp6:188558 VO M00003841A:E09 2012 1034.F06.sp6:188570 VO M00003841B:D05 2013 1034.H06.sp6:188594 VO M00003844C:D04 2014 1034.A07.sp6:188511 VO M00003844C:H05 2015 1034.B07.sp6:188523 VO M00003845A:A05 2016 1034.C07.sp6:188535 VO M00003846B:H02 2017 1034.D07.sp6:188547 VO M00003846D:C12 2018 1034.E07.sp6:188559 VO M00003850B:D11 2019 1034.G07.sp6:188583 VNO 2020 1034.B08.sp6:188524 VO M00003860B:A07 2021 803.D1.sp6:164968 VO M00003862C:H10 2022 803.E1.sp6:164980 VO M00003864B:A04 2023 803.F1.sp6:164992 VNO 2024 803.G1.sp6:165004 VO M00003864D:G05 2025 1034.C08.sp6:188536 VNO 2026 1034.D08.sp6:188548 VO M00003868D:F02 2027 1034.F08.sp6:188572 VO M00003871A:E09 2028 1034.G08.sp6:188584 VNO 2029 1034.H08.sp6:188596 VNO 2030 1034.A09.sp6:188513 VNO 2031 1034.B09.sp6:188525 VO M00003884D:A12 2032 1034.C09.sp6:188537 VNO 2033 1034.D09.sp6:188549 VO M00003887B:C03 2034 1034.E09.sp6:188561 VO M00003888B:A10 2035 1034.F09.sp6:188573 VO M00003888C:E01 2036 1034.G09.sp6:188585 VO M00003890B:H07 2037 1034.H09.sp6:188597 VO M00003890D:C03 2038 1034.A10.sp6:188514 VO M00003892D:D04 2039 1034.B10.sp6:188526 VO M00003893C:D12 2040 1034.D10.sp6:188550 VO M00003896B:F08 2041 1034.E10.sp6:188562 VO M00003896D:B01 2042 1034.F10.sp6:188574 VNO 2043 1034.G10.sp6:188586 VO M00003903C:H03 2044 1034.H10.sp6:188598 VO M00003905C:B01 2045 1034.A11.sp6:188515 VO M00003905C:E10 2046 1034.C11.sp6:188539 VO M00003909D:G01 2047 1034.D11.sp6:188551 VO M00003911C:G05 2048 1034.E11.sp6:188563 VO M00003912B:G11 2049 1034.F11.sp6:188575 VO M00003912C:C11 2050 1034.H11.sp6:188599 VO M00003914C:E03 2051 1034.A12.sp6:188516 VO M00003915A:D09 2052 1034.B12.sp6:188528 VNO 2053 1034.C12.sp6:188540 VO M00003915C:G01 2054 1034.E12.sp6:188564 VO M00003920B:A10 2055 1034.F12.sp6:188576 VNO 2056 1034.G12.sp6:188588 VO M00003921D:C06 2057 1034.H12.sp6:188600 VO M00003923A:H07 2058 1035.A01.sp6:188697 VNO 2059 1035.B01.sp6:188709 VNO 2060 1035.C01.sp6:188721 VO M00003936C:F10 2061 1035.E01.sp6:188745 VO M00003948B:B03 2062 1035.F01.sp6:188757 VO M00003949B:A08 2063 1035.G01.sp6:188769 VO M00003949B:D05 2064 1035.A02.sp6:188698 VO M00003961B:A12 2065 1035.B02.sp6:188710 VO M00003961C:G02 2066 1035.C02.sp6:188722 VO M00003962B:B09 2067 1035.D02.sp6:188734 VO M00003963B:D12 2068 1035.E02.sp6:188746 VO M00003965A:F07 2069 1035.F02.sp6:188758 VNO 2070 1035.H02.sp6:188782 VNO 2071 1035.A03.sp6:188699 VO M00003973A:C05 2072 1035.B03.sp6:188711 VO M00003973B:H06 2073 1035.C03.sp6:188723 VO M00003974B:A04 2074 1035.D03.sp6:188735 VNO 2075 1035.E03.sp6:188747 VNO 2076 1035.F03.sp6:188759 VNO 2077 1035.G03.sp6:188771 VO M00003976D:D12 2078 1035.H03.sp6:188783 VO M00003977C:A08 2079 1035.A04.sp6:188700 VO M00003980B:F12 2080 1035.B04.sp6:188712 VO M00003980C:A11 2081 1035.C04.sp6:188724 VO M00003980C:G10 2082 1035.D04.sp6:188736 VO M00003981C:E04 2083 1035.H04.sp6:188784 VO M00003983C:E07 2084 1035.C05.sp6:188725 VNO 2085 1035.D05.sp6:188737 VO M00003987D:F06 2086 1035.E05.sp6:188749 VO M00003988B:C10 2087 1035.G05.sp6:188773 VNO 2088 803.A2.sp6:164933 VO M00003992C:G01 2089 803.B2.sp6:164945 VO M00003992D:G01 2090 803.C2.sp6:164957 VNO 2091 803.D2.sp6:164969 VO M00003994C:C11 2092 803.E2.sp6:164981 VO M00003996D:C04 2093 803.G2.sp6:165005 VO M00003997D:D07 2094 803.H2.sp6:165017 VNO 2095 803.A3.sp6:164934 VO M00003998A:D03 2096 803.B3.sp6:164946 VO M00003998A:G12 2097 803.C3.sp6:164958 VO M00003998C:H10 2098 803.D3.sp6:164970 VO M00003999C:C12 2099 1035.H05.sp6:188785 VO M00004027A:B10 2100 1035.A06.sp6:188702 VO M00004027C:H01 2101 1035.B06.sp6:188714 VO M00004028C:B04 2102 1035.D06.sp6:188738 VO M00004029A:E01 2103 1035.F06.sp6:188762 VNO 2104 1035.H06.sp6:188786 VO M00004030B:B02 2105 1035.C07.sp6:188727 VO M00004031A:G05 2106 1035.E07.sp6:188751 VO M00004032D:D03 2107 1035.F07.sp6:188763 VNO 2108 1035.G07.sp6:188775 VNO 2109 1035.A08.sp6:188704 VNO 2110 1035.C08.sp6:188728 VO M00004035B:H11 2111 1035.E08.sp6:188752 VO M00004035D:E04 2112 1035.F08.sp6:188764 VO M00004036B:F09 2113 1035.H08.sp6:188788 VO M00004037A:A07 2114 1035.C09.sp6:188729 VO M00004037C:C05 2115 1035.E09.sp6:188753 VO M00004037D:B05 2116 1035.F09.sp6:188765 VO M00004038C:C05 2117 1035.H09.sp6:188789 VO M00004039D:D03 2118 1035.A10.sp6:188706 VO M00004040B:B09 2119 1035.B10.sp6:188718 VO M00004040C:G12 2120 1035.C10.sp6:188730 VO M00004040D:B05 2121 1035.D10.sp6:188742 VO M00004041B:F01 2122 1035.E10.sp6:188754 VO M00004041D:E06 2123 1035.F10.sp6:188766 VO M00004043D:C10 2124 1035.G10.sp6:188778 VNO 2125 803.E3.sp6:164982 VO M00004045A:B12 2126 803.F3.sp6:164994 VO M00004046A:F04 2127 803.G3.sp6:165006 VNO 2128 803.H3.sp6:165018 VNO 2129 803.A4.sp6:164935 VNO 2130 803.B4.sp6:164947 VNO 2131 803.D4.sp6:164971 VNO 2132 803.E4.sp6:164983 VO M00004052C:A08 2133 803.G4.sp6:165007 VO M00004054B:G02 2134 803.H4.sp6:165019 VO M00004054D:A03 2135 803.B5.sp6:164948 VO M00004055B:F06 2136 803.C5.sp6:164960 VO M00004058B:C11 2137 803.E5.sp6:164984 VO M00004058C:E08 2138 803.F5.sp6:164996 VO M00004059A:G09 2139 803.G5.sp6:165008 VO M00004060C:A02 2140 803.H5.sp6:165020 VNO 2141 803.A6.sp6:164937 VO M00004060D:A07 2142 803.B6.sp6:164949 VO M00004063C:B11 2143 803.E6.sp6:164985 VNO 2144 1035.H10.sp6:188790 VO M00004068A:F02 2145 1035.A11.sp6:188707 VO M00004068B:D04 2146 1035.B11.sp6:188719 VNO 2147 1035.C11.sp6:188731 VO M00004069B:B01 2148 1035.D11.sp6:188743 VO M00004069D:G02 2149 1035.E11.sp6:188755 VO M00004071A:H03 2150 1035.F11.sp6:188767 VO M00004073D:B11 2151 1035.G11.sp6:188779 VNO 2152 1035.H11.sp6:188791 VNO 2153 1035.B12.sp6:188720 VNO 2154 1035.D12.sp6:188744 VNO 2155 1035.E12.sp6:188756 VNO 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993.B09.sp6:186531 VO M00005762D:A01 2510 993.C09.sp6:186543 VO M00005763B:H09 2511 993.F09.sp6:186579 VO M00005783A:C05 2512 993.G09.sp6:186591 VO M00005810C:D04 2513 993.H09.sp6:186603 VO M00005812C:F10 2514 993.A10.sp6:186520 VO M00005813D:F06 2515 993.C10.sp6:186544 VO M00005818C:E08 2516 993.D10.sp6:186556 VO M00005818C:G01 2517 993.E10.sp6:186568 VO M00006576D:F11 2518 993.G10.sp6:186592 VO M00006581C:D02 2519 993.H10.sp6:186604 VO M00006581D:H08 2520 993.A11.sp6:186521 VNO 2521 993.B11.sp6:186533 VO M00006582D:E05 2522 993.E11.sp6:186569 VO M00006594A:E08 2523 993.F11.sp6:186581 VO M00006594D:F09 2524 993.H11.sp6:186605 VO M00006596D:H04 2525 993.A12.sp6:186522 VO M00006601C:A07 2526 993.B12.sp6:186534 VO M00006601C:E06 2527 993.C12.sp6:186546 VO M00006601D:F04 2528 993.D12.sp6:186558 VO M00006604C:H10 2529 993.E12.sp6:186570 VO M00006607B:E03 2530 993.F12.sp6:186582 VO M00006607B:F04 2531 993.G12.sp6:186594 VO M00006609A:G10 2532 1010.A01.sp6:189937 VO M00022495C:G05 2533 1010.B01.sp6:189947 VO M00022498C:C08 2534 1010.C01.sp6:189957 VO M00022504B:E03 2535 1010.D01.sp6:189967 VO M00022505D:A12 2536 1010.E01.sp6:189976 VO M00022509D:F06 2537 1010.F01.sp6:189985 VNO 2538 1010.G01.sp6:189994 VO M00022515D:C04 2539 1010.H01.sp6:190003 VO M00022527A:E05 2540 1010.A02.sp6:189938 VO M00022527D:B03 2541 1010.B02.sp6:189948 VO M00022531B:D07 2542 1010.C02.sp6:189958 VO M00022535D:B11 2543 1010.D02.sp6:189968 VO M00022535D:C04 2544 1010.E02.sp6:189977 VO M00022536B:B04 2545 1010.G02.sp6:189995 VO M00022551A:G03 2546 1010.H02.sp6:190004 VO M00022556B:C04 2547 1010.A03.sp6:189939 VO M00022556B:G02 2548 1010.B03.sp6:189949 VNO 2549 1010.C03.sp6:189959 VO M00022562C:H10 2550 1010.D03.sp6:189969 VNO 2551 1010.E03.sp6:189978 VO M00022578B:G05 2552 1010.F03.sp6:189987 VO M00022578C:B07 2553 1010.G03.sp6:189996 VO M00022578D:A08 2554 1010.H03.sp6:190005 VO M00022578D:F03 2555 1010.A04.sp6:189940 VNO 2556 1010.B04.sp6:189950 VO M00022583B:E05 2557 1010.C04.sp6:189960 VO M00022587C:G04 2558 1010.D04.sp6:189970 VO M00022594B:H12 2559 1010.E04.sp6:189979 VO M00022597B:F11 2560 1010.F04.sp6:189988 VO M00022598A:F11 2561 1010.G04.sp6:189997 VNO 2562 1010.H04.sp6:190006 VO M00022599D:E07 2563 1010.A05.sp6:189941 VO M00022600C:A06 2564 1010.B05.sp6:189951 VO M00022604B:C11 2565 1010.C05.sp6:189961 VO M00022607B:A04 2566 1010.D05.sp6:189971 VO M00022613D:C04 2567 1010.E05.sp6:189980 VO M00022651D:C06 2568 1010.F05.sp6:189989 VNO 2569 1010.G05.sp6:189998 VNO 2570 1010.H05.sp6:190007 VO M00022666B:E12 2571 1010.A06.sp6:189942 VO M00022666C:H11 2572 1010.B06.sp6:189952 VNO 2573 1010.C06.sp6:189962 VO M00022681C:H02 2574 1010.D06.sp6:189972 VO M00022682A:F12 2575 1010.E06.sp6:189981 VO M00022685A:F11 2576 1010.F06.sp6:189990 VO M00022698C:E06 2577 1010.G06.sp6:189999 VO M00022701B:B12 2578 1010.H06.sp6:190008 VO M00022708A:C08 2579 1010.A07.sp6:189943 VO M00022708D:G10 2580 1010.B07.sp6:189953 VO M00022716D:D08 2581 1010.C07.sp6:189963 VNO 2582 1010.D07.sp6:189973 VO M00022725C:B03 2583 1010.E07.sp6:189982 VO M00022725C:E09 2584 1010.F07.sp6:189991 VO M00022726A:A06 2585 1010.G07.sp6:190000 VNO 2586 1010.H07.sp6:190009 VNO 2587 1010.A08.sp6:189944 VO M00022730A:E04 2588 1010.B08.sp6:189954 VNO 2589 1010.C08.sp6:189964 VO M00022735B:B01 2590 1010.D08.sp6:189974 VO M00022737A:C08 2591 1010.E08.sp6:189983 VNO 2592 1010.F08.sp6:189992 VO M00022745B:G02 2593 1010.G08.sp6:190001 VO M00022763A:E10 2594 1010.H08.sp6:190010 VO M00022824C:H11 2595 1010.B09.sp6:189955 VO M00022835C:E06 2596 1010.C09.sp6:189965 VO M00022854D:H07 2597 1010.D09.sp6:189975 VO M00022856A:D02 2598 1010.E09.sp6:189984 VNO 2599 1010.F09.sp6:189993 VO M00022856B:F04 2600 1010.G09.sp6:190002 VO M00022856C:B11 2601 1010.H09.sp6:190011 VO M00022893C:H11 2602 1010.A10.sp6:189946 VO M00022897A:F04 2603 1010.B10.sp6:189956 VO M00022900D:E08 2604 1010.C10.sp6:189966 VO M00022900D:G03 2605 019.C4.sp6:128426 VO M00004190A:A09 2606 774.C8.sp6:162530 VO M00004190A:A09 2607 1036.E07.sp6:188943 VO M00004190A:A09 2608 019.E11.sp6:128457 VO M00005817D:E12 2609 993.B10.sp6:186532 VO M00005817D:E12 2610 019.G5.sp6:128475 VO M00006927C:F12

TABLE 1C SEQ ID THC Accession NO: Sequence Name No. 2611 RTA00000587F.p.24.1.Seq THC226834 2612 RTA00000629F.1.02.1.Seq THC210324 2613 RTA00000623F.n.17.1.Seq THC208388 2614 RTA00000593F.i.08.2.Seq H91190 2615 RTA00000622F.b.03.1.Seq AA554045 2616 RTA00000618F.e.06.1.Seq THC226692 2617 RTA00000592F.o.02.1.Seq AA099789 2618 RTA00000618F.c.04.1.Seq THC222808 2619 RTA00000590F.i.01.1.Seq THC173163 2620 RTA00000606F.o.14.1.Seq THC223717 2621 RTA00000626F.d.07.1.Seq THC234888 2622 RTA00000587F.1.08.1.Seq THC104384 2623 RTA00000586F.a.13.1.Seq THC140691 2624 RTA00000617F.a.17.1.Seq THC221850 2625 RTA00000615F.b.23.1.Seq THC205191 2626 RTA00000632F.f.10.1.Seq N39216 2627 RTA00000607F.o.13.2.Seq THC233619 2628 RTA00000622F.c.12.1.Seq THC118482 2629 RTA00000625F.b.07.1.Seq THC223154 2630 RTA00000587F.j.01.1.Seq H63018 2631 RTA00000608F.i.15.1.Seq THC216448 2632 RTA00000592F.j.06.1.Seq THC148215 2633 RTA00000589F.b.14.1.Seq THC158020 2634 RTA00000633F.g.19.1.Seq THC202541 2635 RTA00000620F.o.07.1.Seq THC155200 2636 RTA00000586F.p.01.1.Seq AA558590 2637 RTA00000630F.1.10.1.Seq THC204748 2638 RTA00000626F.c.13.1.Seq AA159259 2639 RTA00000591F.m.06.1.Seq THC227858 2640 RTA00000630F.i.11.1.Seq THC228806 2641 RTA00000621F.h.08.1.Seq THC163604 2642 RTA00000589F.d.10.1.Seq THC177076 2643 RTA00000597F.p.01.1.Seq THC210746 2644 RTA00000619F.c.13.1.Seq R57955 2645 RTA00000607F.c.07.2.Seq THC208762 2646 RTA00000595F.b.02.1.Seq THC233682 2647 RTA00000631F.h.04.1.Seq THC223281 2648 RTA00000596F.p.18.1.Seq THC197103 2649 RTA00000586F.o.13.1.Seq THC222729 2650 RTA00000610F.p.17.1.Seq EST19015 2651 RTA00000596F.c.05.1.Seq E5T72617 2652 RTA00000632F.j.19.1.Seq THC90741 2653 RTA00000607F.e.23.2.Seq AA639216 2654 RTA00000628F.b.19.1.Seq THC118075 2655 RTA00000609F.d.13.1.Seq THC195579 2656 RTA00000621F.k.03.1.Seq EST70278 2657 RTA00000592F.1.04.1.Seq THC91941 2658 RTA00000592F.k.09.1.Seq THC229803 2659 RTA00000622F.e.17.1.Seq R57425 2660 RTA00000628F.g.13.1.Seq THC176706 2661 RTA00000592F.k.23.1.Seq THC232202 2662 RTA00000609F.m.04.2.Seq AA507611 2663 RTA00000626F.b.04.1.Seq EST69420 2664 RTA00000591F.m.01.1.Seq H41850 2665 RTA00000608F.n.23.1.Seq THC214886 2666 RTA00000583F.d.19.1.Seq THC229251 2667 RTA00000621F.p.15.1.Seq THC212450 2668 RTA00000583F.n.05.1.Seq AA252468 2669 RTA00000597F.f.17.1.Seq THC219322 2670 RTA00000606F.1.10.1.Seq THC225232 2671 RTA00000618F.n.14.1.Seq THC216591 2672 RTA00000612F.h.05.3.Seq THC158250 2673 RTA00000619F.a.24.1.Seq AA437370 2674 RTA00000617F.k.13.1.Seq AA244445 2675 RTA00000623F.h.07.1.Seq THC212330 2676 RTA00000620F.e.01.1.Seq THC167493 2677 RTA00000620F.h.10.1.Seq THC232456 2678 RTA00000589F.e.21.2.Seq THC208239 2679 RTA00000626F.b.22.1.Seq THC225644 2680 RTA00000620F.i.16.1.Seq AA536090 2681 RTA00000613F.c.17.1.Seq THC92470 2682 RTA00000621F.c.12.1.Seq THC156244 2683 RTA00000618F.b.17.1.Seq THC209838 2684 RTA00000585F.d.16.1.Seq THC211870 2685 RTA00000592F.a.06.1.Seq THC233200 2686 RTA00000583F.p.08.1.Seq THC196844 2687 RTA00000622F.h.21.1.Seq EST12698 2688 RTA00000591F.h.03.1.Seq THC213771 2689 RTA00000620F.g.22.1.Seq THC224063 2690 RTA00000588F.1.20.2.Seq R84876 2691 RTA00000614F.a.20.1.Seq R84876 2692 RTA00000611F.n.14.3.Seq THC200742 2693 RTA00000619F.f.23.1.Seq THC227573 2694 RTA00000608F.g.24.1.Seq T93977 2695 RTA00000595F.o.01.2.Seq EST61392 2696 RTA00000608F.b.23.1.Seq THC161665 2697 RTA00000606F.o.23.1.Seq AA464645 2698 RTA00000588F.i.22.3.Seq THC162216 2699 RTA00000610F.i.13.1.Seq AA595068 2700 RTA00000608F.b.15.1.Seq EST11866 2701 RTA00000597F.e.16.1.Seq N88730 2702 RTA00000610F.h.13.1.Seq THC195895 2703 RTA00000611F.h.21.2.Seq EST46722 2704 RTA00000584F.b.06.1.Seq EST02998 2705 RTA00000584F.b.06.2.Seq EST02998 2706 RTA00000608F.j.05.1.Seq EST60433 2707 RTA00000588F.b.03.1.Seq THC164651

TABLE 2A Nearest Neighbor (BlastN vs. Genbank) SEQ ID ACC'N DESCRIP. P VALUE 571 L17043 Homo sapiens pregnancy-specific beta-1-glycoprotein-11 gene. 1.00E−12 578 M18864 Rat bone protein I (BP-I) mRNA, partial cds. 7.00E−30 609 L13838 Human genomic sequence from chromosome 13, clone 4.00E−36 ch13lambdacDNA17–18. 618 U09646 Human carnitine palmitoyltransferase II precursor 1.00E−34 627 U72621 Human LOT1 mRNA, complete cds 1.00E−43 629 M20910 Human 7S L gene, complete. 1.00E−35 636 Z48950 H.sapiens hH3.3B gene for histone H3.3 4.00E−36 639 X00247 Human translocated c-myc gene in Raji Burkitt lymphoma cells 3.00E−44 643 D80007 Human mRNA for KIAA0185 gene, partial cds 7.00E−52 646 U14967 Human ribosomal protein L21 mRNA, complete cds. 2.00E−42 649 M13934 Human ribosomal protein S14 gene, complete cds. 4.00E−45 652 NM_003902 Homo sapiens far upstream element binding protein (FUBP) 1.00E−54 .1 mRNA > :: gb|U05040|HSU05040 Human FUSE binding protein mRNA, complete cds. 657 L41142 Homo sapiens signal transducer and activator of transcription 2.00E−62 (STAT5) mRNA, complete cds. 665 Z12112 pWE15A cosmid vector DNA 2.00E−52 667 Z54386 H.sapiens CpG island DNA genomic Mse1 fragment, clone 7.00E−48 10g3, forward read cpg10g3.ft1a 668 X80333 M.musculus rab18 mRNA 2.00E−52 669 X52126 Human alternatively spliced c-myb mRNA 1.00E−64 671 L26247 Homo sapiens sui1iso1 mRNA, complete cds. 3.00E−54 676 NM_001736 Homo sapiens complement component 5 receptor 1 C5a 4.00E−56 .1 anaphylatoxin receptor mRNA, complete cds. 677 Z50798 G.gallus mRNA for p52 4.00E−55 679 AB002368 Human mRNA for KIAA0370 gene, partial cds 2.00E−58 681 M26697 Human nucleolar protein (B23) mRNA, complete cds. 4.00E−48 683 D42087 Human mRNA for KIAA0118 gene, partial cds 4.00E−56 693 D50734 Rat mRNA of antizyme inhibitor, complete cds 2.00E−50 697 X02344 Homo sapiens beta 2 gene 1.00E−67 698 NM_001067 Homo sapiens topoisomerase (DNA) II alpha topoisomerase II 7.00E−63 .1 (top2) mRNA, complete cds. 701 U36309 Gallus gallus rhoGap protein mRNA, complete cds 3.00E−62 703 NM_002842 Homo sapiens protein tyrosine phosphatase, receptor type, H 2.00E−81 .1 (PTPRH) mRNA > :: dbj|D15049|HUMSAP1C Human mRNA for protein tyrosine phosphatase 707 U47322 Cloning vector DNA, complete sequence. 1.00E−63 Homo sapiens branched chain aminotransferase 2. mitochondrial 714 NM_001190 (BCAT2) mRNA > :: gb|U68418|HSU68418 Human branched 4.00E−67 .1 chain aminotransferase precursor (BCATm) mRNA, nuclear gene encoding mitochondrial protein, complete cds 718 S62077 HP1Hs alpha = 25 kda chromosomal autoantigen [human, mRNA, 5.00E−68 876 nt] 719 U34991 Human endogenous retrovirus clone c18.4, HERV-H/HERV-E 2.00E−61 hybrid multiply spliced protease/integrase mRNA, complete cds, and envelope protein mRNA, partial cds 722 U18671 Human Stat2 gene, complete cds. 4.00E−77 723 L18964 Human protein kinase C iota isoform (PRKCI) mRNA, complete 4.00E−68 cds. 724 D29956 Human mRNA for KIAA0055 gene, complete cds 6.00E−70 725 M77140 H.sapiens pro-galanin mRNA, 3′ end. 2.00E−72 728 U51432 Homo sapiens nuclear protein Skip mRNA, complete cds 1.00E−75 729 M84334 Macacca mulatta hnRNP A1-gamma isoform mRNA, complete 5.00E−50 cds. 730 NM_002592 Homo sapiens proliferating cell nuclear antigen (PCNA) mRNA >:: 1.00E−74 .1 gb|M15796|HUMCYL Human cyclin protein gene, complete cds. 731 M88458 Human ELP-1 mRNA sequence. 4.00E−76 732 U44940 Mus musculus quaking type I (QKI) mRNA, complete cds 2.00E−69 733 D17577 Mouse mRNA for kinesin-like protein (Kif1b), complete cds 2.00E−71 734 U18920 Human chromosome 17q12-21 mRNA, clone pOV-3, partial cds. 2.00E−72 736 M21188 Human insulin-degrading enzyme (IDE) mRNA, complete cds. 7.00E−82 737 U49058 Rattus norvegicus CTD-binding SR-like protein rA4 mRNA, 1.00E−67 partial cds 739 D10630 Mus musculus mRNA for zinc finger protein, complete cds, 4.00E−76 clone:CTfin51 740 U29156 Mus musculus eps15R mRNA, complete cds. 3.00E−84 741 Y08135 M.musculus mRNA for ASM-like phosphodiesterase 3a 1.00E−86 742 U90567 Gallus gallus glutamine rich protein mRNA, partial cds 5.00E−58 743 U58280 Mus musculus second largest subunit of RNA polymerase I 4.00E−77 (RPA2) mRNA, complete cds 744 S79539 Pat-12 = Pat-12 product [mice, embryonic stem ES cells, mRNA, 9.00E−84 2781 nt] 745 D30666 Rat mRNA for brain acyl-CoA synthetase II, complete cds 2.00E−89 746 U29156 Mus musculus eps15R mRNA, complete cds. 2.00E−92 748 U36909 Bos taurus Rho-associated kinase mRNA, complete cds e-104 749 L36315 Mus musculus (clone pMLZ-1) zinc finger protein e-105 750 X80169 M.musculus mRNA for 200 kD protein e-106 751 X83577 M.musculus mRNA for K-glypican e-107 1060 Z95437 Human DNA sequence from cosmid A1 on chromosome 6 8.00E−21 contains ESTs. HERV like retroviral sequence 1112 X69907 H.sapiens gene for mitochondrial ATP synthase c subunit (P1 6.00E−07 form) 1125 M19390 Bovine interstitial retinol binding protein 8.00E−31 1156 U19247 Homo sapiens interferon-gamma receptor alpha chain gene, exon 7.00E−41 7 and complete cds 1170 U20239 Mus musculus fibrosin mRNA, partial cds 5.00E−38 1171 D26361 Human mRNA for KIAA0042 gene, complete cds 2.00E−41 1195 NM_000694 Homo sapiens aldehyde dehydrogenase 7 (ALDH7) mRNA > :: 1.00E−37 .1 gb|U10868|HSU10868 Human aldehyde dehydrogenase ALDH7 mRNA, complete cds. 1196 U84404 Human E6-associated protein E6-AP/ubiquitin-protein ligase 1.00E−46 (UBE3A) mRNA, alternatively spliced, complete cds 1203 U51714 Human GPI protein p137 mRNA, partial sequence, 3′-UTR. 9.00E−53 1204 U58884 Mus musculus SH3-containing protein SH3P7 mRNA, complete 2.00E−49 cds. similar to Human Drebrin 1210 X79067 H.sapiens ERF-1 mRNA 3′ end 2.00E−72 1212 U00946 Human clone A9A2BRB5 (CAC)n/(GTG)n repeat-containing 3.00E−54 mRNA 1217 D11078 Homo sapiens RGH2 gene, retrovirus-like element 6.00E−49 1219 U05989 Rattus norvegicus clone par-4 induced by effectors of apoptosis 3.00E−64 mRNA, complete cds. 1220 U13185 Cloning vector pbetagal-Enhancer, complete sequence. 3.00E−52 1222 D87443 Human mRNA for KIAA0254 gene, complete cds 8.00E−63 1225 U19867 Cloning vector pSPL3, exon splicing vector, complete sequence, 7.00E−72 HIV envelope protein gp160 and beta-lactamase, complete cds. 1227 U04817 Human protein kinase PITSLRE alpha 2–3 mRNA, complete cds. 4.00E−57 1230 U03687 Photinus pyralis modified luciferase gene, complete cds, and 3.00E−62 pUC18 derived vector. 1231 U27196 Gallus gallus zinc finger protein (Fzf-1) mRNA, complete cds. 1.00E−66 1235 X53586 Human mRNA for integrin alpha 6 2.00E−71 1236 J05016 Human (clone pA3) protein disulfide isomerase related protein 3.00E−67 (ERp72) mRNA, complete cds. 1237 M86752 Human transformation-sensitive protein (IEF SSP 3521) mRNA, 1.00E−66 complete cds. 1239 L19437 Human transaldolase mRNA containing transposable element, 5.00E−70 complete cds 1241 X90857 H.sapiens mRNA for −14 gene, containing globin regulatory 1.00E−74 element 1242 NM_003980 Homo sapiens microtubule associated protein 7 mRNA 9.00E−76 .1 1245 U17901 Rattus norvegicus phospholipase A-2-activating protein (plap) 3.00E−75 mRNA, complete cds. 1246 S80632 threonine, tyrosine phosphatase [human, brain, mRNA Partial, 2.00E−69 1236 nt] 1247 M76541 Human DNA-binding protein (NF-E1) mRNA, complete cds. 2.00E−80 1248 S55305 14-3-3 protein gamma subtype = putative protein kinase C 7.00E−93 regulatory protein [rats, brain, mRNA, 3410 nt] > :: dbj|D17447|D17447 Rattus norvegicus mRNA for 14-3-3 protein gamma-subtype, complete cds 1249 NM_002350 Homo sapiens v-yes-1 Yamaguchi sarcoma viral related 3.00E−86 .1 oncogene homolog (LYN) mRNA > :: gb|M16038|HUMLYN Human lyn mRNA encoding a tyrosine kinase. 1250 Y10725 M.musculus mRNA for protein kinase KIS 4.00E−68 1251 U89931 Cloning vector pTRE, complete sequence 3.00E−65 1252 Z46386 Bovine herpesvirus type 4 DNA for nonconserved region F 3.00E−73 (DN599 like strain) 1253 L77599 Homo sapiens (clone SEL214) 17q YAC (303G8) RNA. 2.00E−69 1255 Y10746 H.sapiens mRNA for protein containing MBD 1 2.00E−79 1256 L77599 Homo sapiens (clone SEL214) 17q YAC (303G8) RNA. 2.00E−71 1257 Z57619 H.sapiens CpG island DNA genomic Mse1 fragment, clone 7.00E−72 187a6, forward read cpg187a6.ft1b 1258 U48807 Human MAP kinase phosphatase (MKP-2) mRNA, complete cds 3.00E−76 1260 M27444 Bos taurus (clone pTKD7) dopamine and cyclic AMP-regulated 4.00E−76 neuronal phosphoprotein (DARPP-32) mRNA, complete cds. 1261 U37150 Bos taurus peptide methionine sulfoxide reductase (msrA) 5.00E−78 mRNA, complete cds 1262 U02435 Cloning vector pSVbeta, complete sequence 1.00E−77 1263 U09662 Cloning vector pSEAP-Enhancer, complete sequence 4.00E−79 1264 M99566 sCos cloning vector SfiI containing bacteriophage promoters and 1.00E−79 flanking restriction sites in sCos vectors. 1266 Z12112 pWE15A cosmid vector DNA 4.00E−80 1267 U55387 Cricetulus griseus SL15 mRNA, complete cds 2.00E−82 Rattus norvegicus nuclear-encoded mitochondrial elongation 2.00E−91 1269 L14684 factor G mRNA, complete cds. 1270 U49057 Rattus norvegicus CTD-binding SR-like protein rA9 mRNA, 7.00E−93 complete cds 1271 U57368 Mus musculus EGF repeat transmembrane protein mRNA, 4.00E−97 complete cds. 1272 AF000938 Mus musculus RNA polymerase I largest subunit 8.00E−94 1274 X80169 M.musculus mRNA for 200 kD protein e-102 1275 U09874 Mus musculus SKD3 mRNA, complete cds. e-105 1276 D78020 Rat mRNA for NFI-A4, partial cds e-108 1515 Z73360 Human DNA sequence from cosmid 92M18, BRCA2 gene 9.00E−22 region chromosome 13q12-13 1522 X62078 H.sapiens mRNA for GM2 activator protein 7.00E−72 1523 X85750 H.sapiens mRNA for transcript associated with monocyte to 2.00E−50 macrophage differentiation 1525 X03473 Human gene for histone H1(0) 1.00E−67 1535 X64411 R.norvegicus mRNA for 100 kDa protein 1.00E−54 1538 X13345 Human gene for plasminogen activator inhibitor 1 2.00E−59 1542 D86971 Human mRNA for KIAA0217 gene, partial cds 7.00E−83 1543 NM_001859 Homo sapiens solute carrier family 31 gb|U83460|HSU83460 7.00E−72 .1 Human high-affinity copper uptake protein (hCTR1) mRNA, complete cds 1544 X68194 H.sapiens h-Sp1 mRNA 5.00E−57 1545 AB002326 Human mRNA for KIAA0328 gene, partial cds 3.00E−74 1548 D31762 Human mRNA for KIAA0057 gene, complete cds 3.00E−85 1550 X58472 Mouse KIN17 mRNA for kin17 protein 2.00E−57 1551 U13185 Cloning vector pbetagal-Enhancer, complete sequence. 2.00E−79 1552 U55939 Expression vector pVP-Nco, complete sequence. 1.00E−76 1553 D87671 Rattus norvegicus mRNA for TIP120, complete cds 1.00E−87 1554 U25691 Mus musculus lymphocyte specific helicase mRNA, complete 4.00E−86 cds 1555 U55939 Expression vector pVP-Nco, complete sequence. 5.00E−79 1556 Z12112 pWE15A cosmid vector DNA 2.00E−79 1557 U13185 Cloning vector pbetagal-Enhancer, complete sequence. 2.00E−79 1558 U13185 Cloning vector pbetagal-Enhancer, complete sequence. 6.00E−80 1559 Z12112 pWE15A cosmid vector DNA 6.00E−80 1560 U09661 Cloning vector pSEAP-Control, complete sequence 6.00E−80 1561 U36909 Bos taurus Rho-associated kinase mRNA, complete cds 2.00E−90 1562 L36610 Mus musculus protein synthesis initiation factor 4A (elF-4A) 2.00E−71 gene, exons 5, 6, 7, 8, and 9. 1563 S79463 M-Sema F = a factor in neural network development 1.00E−85 Mus musculus nuclear receptor co-repressor mRNA, complete 1564 U35312 cds 1.00E−98 1571 L32977 Homo sapiens (clone f17252) ubiquinol cytochrome c reductase 0 Rieske iron-sulphur protein (UQCRFS1) gene, exon 2 1576 S78454 Mus musculus metal response element DNA-binding protein 0 M96 mRNA, complete cds 1586 M88458 Human ELP-1 mRNA sequence. 0 1622 S77512 LAMB2 = laminin beta 2 chain [human, placenta, mRNA, 5642 e-131 nt] 1624 X53305 H.sapiens mRNA for statlimin 0 1625 J03591 Human ADP/ATP translocase mRNA, 3′ end, clone pHAT3. 0 1630 L18964 Human protein kinase C iota isoform (PRKCI) mRNA, complete 2E−67 cds. 1640 D29956 Human mRNA for KIAA0055 gene, complete cds 0 1649 M26697 Human nucleolar protein (B23) mRNA, complete cds. e-149 1669 U47322 Cloning vector DNA, complete sequence. 4E−65 1689 NM_002079 Homo sapiens glutamic-oxaloacetic transaminase 1, soluble 0 .1 (aspartate aminotransferase 1) aspartate aminotransferase mRNA, complete cds. 1693 U55939 Expression vector pVP-Nco, complete sequence. 2E−70 1694 D80007 Human mRNA for KIAA0185 gene, partial cds 0 1695 NM_001904 Homo sapiens catenin (cadherin-associated protein), beta 1 e-108 .1 (88kD) (CTNNB1) mRNA > :: emb|X87838|HSRNABECA H.sapiens mRNA for beta-catenin 1701 U19867 Cloning vector pSPL3, exon splicing vector, complete sequence, 1E−44 HIV envelope protein gp160 and beta-lactamase, complete cds. 1702 M31061 Human ornithine decarboxylase gene, complete cds. 0 1721 Z96177 H.sapiens telomeric DNA sequence, clone 10QTEL040, read 2E−70 10QTELOO040.seq 1722 NM_001904 Homo sapiens catenin (cadherin-associated protein), beta 1 e-176 .1 (88 kD) (CTNNB1) mRNA > :: emb|X87838|HSRNABECA H.sapiens mRNA for beta-catenin 1758 X83577 M.musculus mRNA for K-glypican 0 1761 S79539 Pat-12 = Pat-12 product [mice, embryonic stem ES cells, mRNA, e-176 2781 nt] 1773 L38951 Homo sapiens importin beta subunit mRNA, complete cds 1E−78 NM_003902 Homo sapiens far upstream element binding protein (FUBP) mRNA > :: gb|U05040|HSU05040 Human FUSE binding protein 1776 .1 mRNA, complete cds. 0 1791 L08783 BlueScribe M13 Plus cloning vector. 0 1809 U86751 Human nucleolar fibrillar center protein (ASE−1) mRNA, 8E−95 complete cds 1817 M21188 Human insulin-degrading enzyme (IDE) mRNA, complete cds. e-134 1831 NM_001614 Homo sapiens actin, gamma 1 (ACTG1) mRNA > :: 0.00E+00 .1 emb|X04098|HSACTCGR Human mRNA for cytoskeletal gamma-actin 1836 U12404 Human Csa-19 mRNA, complete cds. 0 1837 X79236 H.sapiens rps26 gene e-145 1838 NM_003313 Homo sapiens tissue specific transplantation antigen P35B 0 .1 (TSTA3) mRNA > :: gb|U58766|HSU58766 Human FX protein mRNA, complete cds 1839 M27436 Human tissue factor gene, complete cds, with a Alu repetitive e-121 sequence in the 3′ untranslated region. > :: gb|105724| Sequence 12 from Patent EP 0278776 1849 X79067 H.sapiens ERF-1 mRNA 3′ end 0 1850 NM_003017 Homo sapiens splicing factor, arginine/serine-rich 3 (SFRS3) e-135 .1 mRNA > :: gb|L10838|HUMSRP20 Homo sapiens SR protein family, pre-mRNA splicing factor (SRp20) mRNA, complete cds. 1857 U48807 Human MAP kinase phosphatase (MKP-2) mRNA, complete cds 0.00E+00 1858 U48807 Human MAP kinase phosphatase (MKP-2) mRNA, complete cds 0.00E+00 1873 U04817 Human protein kinase PITSLRE alpha 2–3 mRNA, complete cds. 8.00E−53 1876 U18297 Human MST1 (MST1) mRNA, complete cds. 0.00E+00 1877 NM_001859 Homo sapiens solute carrier family 31 gb|U83460|HSU83460 0 .1 Human high-affinity copper uptake protein (hCTR1) mRNA, complete cds 1889 X70272 single stranded replicative centromeric Saccharomyces 3.00E−76 cerevisiae/E. coli shuttle vector 1897 L26050 Human mitochondrial 2,4-dienoyl-CoA reductase mRNA, 0.00E+00 complete cds. 1899 X06747 Human hnRNP core protein A1 e-157 1901 M64571 Human microtubule-associated protein 4 mRNA, complete cds. 0.00E+00 1908 X65322.1 Cloning vector pCAT-Basic 9.00E−53 Homo sapiens pyruvate kinase, muscle (PKM2) mRNA > :: 1913 NM_002654 gb|M23725|HUMPKM2L Human M2-type pyruvate kinase e-159 .1 mRNA, complete cds. 1916 U49352 Human liver 2,4-dienoyl-CoA reductase mRNA, complete cds 2.00E−71 1926 D31889 Human mRNA for KIAA0072 gene, partial cds > :: e-167 gb|G27027|G27027 human STS SHGC-31585. 1941 U43944 Human breast cancer cytosolic NADP(+)-dependent malic 1.00E−89 enzyme mRNA, partial cds 1971 U83659 Human multidrug resistance-associated protein homolog (MRP3) 3.00E−85 mRNA, partial cds 1996 M33519 Human HLA-B-associated transcript 3 (BAT3) mRNA, complete 3.00E−84 cds. 1997 U55387 Cricetulus griseus SL15 mRNA, complete cds e-150 2018 L36315 Mus musculus (clone pMLZ-1) zinc finger protein e-162 2025 NM_003902 Homo sapiens far upstream element binding protein (FUBP) e-175 .1 mRNA > :: gb|U05040|HSU05040 Human FUSE binding protein mRNA, complete cds. 2032 X56932 H.sapiens mRNA for 23 kD highly basic protein 0.00E+00 2039 X98654 H.sapiens mRNA for DRES9 protein 9.00E−97 2050 S62077 HP1Hs alpha = 25 kda chromosomal autoantigen [human, mRNA, 4.00E−68 876 nt] 2057 M23619 Human HMG-I protein isoform mRNA (HMGI gene), clone 6A. e-117 2077 NM_003217 Homo sapiens testis enhanced gene transcript 4E−99 .1 2092 U18671 Human Stat2 gene, complete cds. 0.00E+00 2096 D43636 Human mRNA for KIAA0096 gene, partial cds 0 2098 NM_002734 Homo sapiens protein kinase, cAMP-dependent, regulatory, type 0 .1 I, alpha (tissue specific extinguisher 1) (PRKAR1A) mRNA > :: gb|M33336|HUMCAMPPK Human cAMP-dependent protein kinase type 1-alpha subunit 2099 U72621 Human LOT1 mRNA, complete cds 0.00E+00 2112 NM_003902 Homo sapiens far upstream element binding protein (FUBP) 0.00E+00 .1 mRNA > :: gb|U05040|HSU05040 Human FUSE binding protein mRNA, complete cds. 2118 L41142 Homo sapiens signal transducer and activator of transcription 0.00E+00 (STAT5) mRNA, complete cds. 2119 Z48950 H.sapiens hH3.3B gene for histone H3.3 0.00E+00 2153 L09260 Human (chromosome 3p25) membrane protein mRNA. e-100 2158 X65304.1 Cloning vector pGEM-3Z e-173 Homo sapiens UDP-glucose ceramide glucosyltransferase (UGCG) mRNA > :: dbj|D50840|HUMCGA Homo sapiens 2163 NM_003358 mRNA for ceramide glucosyltransferase, complete cds > :: e-141 .1 dbj|E12454|E12454 cDNA encoding human ceramide glucosyltransferase 2179 M95605 Bos taurus S-adenosylmethionine decarboxylase e-175 2180 M12623 Human non-histone chromosomal protein HMG-17 mRNA, 0.00E+00 complete cds. 2181 U79143 Human phosphoinositide 3′-hydroxykinase p110-alpha subunit 0.00E+00 mRNA, complete cds 2192 K01906 Human fetal liver c-myc proto-oncogene, exon 3 and flanks. e-165 2194 X74870 H.sapiens gene for RNA pol II largest subunit, exons 23–29 e-161 2235 L16991 Human thymidylate kinase (CDC8) mRNA, complete cds. 0.00E+00 2257 L08783 BlueScribe M13 Plus cloning vector. 0.00E+00 2276 NM_002245 Homo sapiens potassium inwardly-rectifying channel, subfamily 0 .1 K, member 1 (KCNK1) mRNA > :: gb|U33632|HSU33632 Human two P-domain K+ channel TWIK-1 mRNA, complete cds. 2278 D50734 Rat mRNA of antizyme inhibitor, complete cds e-157 2279 U26401 Human galactokinase (galK) mRNA, complete cds. > 0.00E+00 2285 U49058 Rattus norvegicus CTD-binding SR-like protein rA4 mRNA, e-138 partial cds 2287 X65306.1 Cloning vector pGEM-3Zf(+) e-116 2299 NM_001172 Homo sapiens arginase, type II (ARG2) mRNA > :: e-127 .1 gb|U82256|HSU82256 Homo sapiens arginase type II mRNA, complete cds 2309 M25160 Human Na,K-ATPase beta subunit (ATP1B) gene, exons 3 0.00E+00 through 6. 2315 Y08736 H.sapiens vegf gene, 3′UTR 1.00E−78 2320 U13737 Human cysteine protease CPP32 isoform alpha mRNA, complete 0.00E+00 cds. 2323 Y08135 M.musculus mRNA for ASM-like phosphodiesterase 3a e-148 2324 Y08135 M.musculus mRNA for ASM-like phosphodiesterase 3a 0 2328 NM_001677 Homo sapiens ATPase, Na+/K+ transporting, beta 1 polypeptide 1E−77 .1 (ATP1B1) mRNA > :: emb|X03747|HSATPBR Human mRNA for Na/K-ATPase beta subunit 2337 Y08135 M.musculus mRNA for ASM-like phosphodiesterase 3a e-168 2364 U54778 Human 14-3-3 epsilon mRNA, complete cds 1E−67 2365 Y08135 M.musculus mRNA for ASM-like phosphodiesterase 3a 0 NM_001172 Homo sapiens arginase, type II (ARG2) mRNA > :: gb|U82256|HSU82256 Homo sapiens arginase type II mRNA, 2368 .1 complete cds e-127 2385 AB002293 Human mRNA for KIAA0295 gene, partial cds 0 2394 M21188 Human insulin-degrading enzyme (IDE) mRNA, complete cds. 2E−81 2425 D87466 Human mRNA for KIAA0276 gene, partial cds 1E−97 2429 U58884 Mus musculus SH3-containing protein SH3P7 mRNA, complete 4E−96 cds. similar to Human Drebrin 2441 AB005216 Homo sapiens mRNA for Nck, Ash and phospholipase C gamma- 0 binding protein NAP4, partial cds 2442 NM_001960 Homo sapiens eukaryotic translation elongation factor 1 delta 0.00E+00 .1 (guanine nucleotide exchange protein) (EEF1D) mRNA > :: emb|Z21507|HSEF1DELA H.sapiens EF-1delta gene encoding human elongation factor-1-delta 2444 M92449 Human LTR mRNA, 3′ end of coding region and 3′ flank. e-143 2452 NM_003350 Homo sapiens ubiquitin-conjugating enzyme E2 variant 2 0 .1 (UBE2V2) mRNA > :: emb|X98091|HSVITDITR H.sapiens mRNA for protein induced by vitamin D 2456 U44975 Homo sapiens DNA-binding protein CPBP (CPBP) mRNA, 5.00E−69 partial cds 2459 Z84510 H.sapiens flow-sorted chromosome 6 HindIII fragment, 4.00E−66 SC6pA28B7 2463 Z48042 H.sapiens mRNA encoding GPI-anchored protein p137 e-172 2497 U32986 Human xeroderma pigmentosum group E UV-damaged DNA 0 binding factor mRNA, complete cds. 2515 NM_003419 Homo sapiens zinc finger protein 10 (KOX 1) for zinc finger e-129 .1 protein 2520 Y00711 Human mRNA for lactate dehydrogenase B (LDH-B) 0.00E+00 2526 Y10725 M.musculus mRNA for protein kinase KIS 0.00E+00 2543 X62078 H.sapiens mRNA for GM2 activator protein e-164 2548 NM_001009 Homo sapiens ribosomal protein S5 (RPS5) mRNA complete 0.00E+00 .1 cds. 2556 U97188 Homo sapiens putative RNA binding protein KOC 1E−86 2575 NM_002852 Homo sapiens pentaxin-related gene, rapidly induced by IL-1 0.00E+00 .1 beta (PTX3) mRNA > :: emb|X63613|HSPTX3R H.sapiens mRNA for pentaxin (PTX3) 2578 X67155 H.sapiens mRNA for mitotic kinesin-like protein-1 0.00E+00 2588 M54968 Human K-ras oncogene protein mRNA, complete cds > e-123 2591 D88687 Homo sapiens mRNA for KM-102-derived reductase-like factor, 0 complete cds NM_001436 Homo sapiens fibrillarin (FBL) mRNA > :: gb|M59849|HUMFIBAA Human fibrillarin (Hfib1) mRNA, 2593 .1 complete cds. e-103 2595 AB002326 Human mRNA for KIAA0328 gene, partial cds 0.00E+00 2598 M11948 Human promyelocytic leukemia cell mRNA, clones pHH58 and 9.00E−84 pHH81.

TABLE 2B Nearest Neighbor (BlastX vs. Non-Redundant Proteins) SEQ ID ACC'N DESCRIP. P VALUE 37 4239895 (AB016816) MASL1 [Homo sapiens] 9.00E−54 66 4514653 (AB024057) vascular Rab-GAP/TBC-containing protein 6.00E−55 [Homo sapiens] 78 4454524 (AC004841) similar to insulin receptor substrate BAP2; 6.00E−22 similar to PID:g4126477 [Homo sapiens] 79 4545264 (AF118240) peroxisomal biogenesis factor 16 [Homo sapiens] 1.00E−45 112 3413938 (AB007963) KIAA0494 protein [Homo sapiens] 3.00E−44 122 4239895 (AB016816) MASL1 [Homo sapiens] 1.00E−47 139 4502371 breast cancer antiestrogen resistance 3 > gi|3237306 (U92715) 2.00E−44 breast cancer antiestrogen resistance 3 protein [Homo sapiens] 154 4586880 (AB017114) AD 3 [Homo sapiens] 4.00E−48 157 3327170 (AB014578) KIAA0678 protein [Homo sapiens] 2.00E−51 168 3153241 (AF053004) class I cytokine receptor [Homo sapiens] 2.00E−17 171 4138233 (AJ007780) parp-2 gene [Mus musculus] 2.00E−32 174 3287173 (AJ006266) AND-1 protein [Homo sapiens] 2.00E−42 187 4507145 UNKNOWN > gi|3873216 (AF065485) sorting nexin 4 [Homo 8.00E−46 sapiens] 207 4153860 (AC005074) similar to U47321 (PID:g1245146) [Homo 4.00E−15 sapiens] 224 3236430 (AF067379) ubiquitin-protein ligase E3-alpha [Mus musculus] 3.00E−35 253 3043696 (AB011158) KIAA0586 protein [Homo sapiens] 1.00E−44 260 4519623 (AB017616) homologous to the yeast YGR163 gene [Mus 2.00E−54 musculus] 280 4455035 (AF116238) pseudouridine synthase 1 [Homo sapiens] 4.00E−48 304 3075377 (AC004602) F23487_2 [Homo sapiens] 2.00E−21 306 4505611 poly(A)-specific ribonuclease 7.00E−41 373 1825606 (U88169) similar to molybdoterin biosynthesis MOEB 2.00E−37 proteins [Caenorhabditis elegans] 382 4586287 (AB004794) DUF140 [Xenopus laevis] 7.00E−45 396 3941342 (AF043250) mitochondrial outer membrane protein [Homo 5.00E−40 sapiens] > gi|3941347 (AF043253) mitochondrial outer membrane protein [Homo sapiens] > gi|4105703|gb|AAD02504| 414 4586844 (AB015633) type II membrane protein 2.00E−46 422 3327078 (AB014532) KIAA0632 protein [Homo sapiens] 6.00E−36 433 3327230 (AB014608) KIAA0708 protein [Homo sapiens] 5.00E−52 472 3372677 (AF061749) tumorous imaginal discs protein Tid56 homolog 7.00E−35 502 4050034 (AF098482) transcriptional coactivator p52 [Homo sapiens] 1.00E−36 504 4406632 (AF131801) Unknown [Homo sapiens] 3.00E−21 512 3114828 (AJ005897) JM5 [Homo sapiens] 3.00E−44 530 3766209 (AF071777) IRE1 [Mus musculus] 2.00E−29 561 3043644 (AB011132) KIAA0560 protein [Homo sapiens] 3.00E−43 572 3088575 (AF059531) protein arginine N-methyltransferase 3 [Homo 4.00E−46 sapiens] 578 4505891 UNKNOWN > gi|3153235 (AF046889) lysyl hydroxylase 3.00E−30 isoform 3 [Homo sapiens] > gi|3551836 590 3114828 (AJ005897) JM5 [Homo sapiens] 1.00E−24 592 3242214 (AJ006778) DRIM protein [Homo sapiens] 2.00E−36 598 4200236 (AL035308) hypothetical protein [Homo sapiens] 8.00E−09 600 3413892 (AB007934) KIAA0465 protein [Homo sapiens] 2.00E−51 635 3043626 (AB011123) KIAA0551 protein [Homo sapiens] 3.00E−31 643 2498864 RRP5 PROTEIN HOMOLOG (KIAA0185) hypothetical 3.00E−13 protein YM9959.11C of S.cerevisiae. [Homo sapiens] 670 3402197 (AJ010014) M96A protein [Homo sapiens] 1.00E−21 677 2217964 (Z50798) p52 [Gallus gallus] 7.00E−14 686 3043626 (AB011123) KIAA0551 protein [Homo sapiens] 1.00E−40 697 135470 TUBULIN BETA-5 CHAIN sapiens] 3.00E−21 701 3327056 (AB014521) KIAA0621 protein [Homo sapiens] 2.00E−29 704 4506787 UNKNOWN GTPASE-ACTIVATING-LIKE PROTEIN 4.00E−41 IQGAP1 (P195) (KIAA0051) protein-human > gi|473931|dbj|BAA06123| (D29640) KIAA0051 [Homo sapiens] > gi|536844 (L33075) ras GTPase-activating-like protein [Homo sapiens] 709 1350762 60S RIBOSOMAL PROTEIN L6 sapiens] 2.00E−22 713 2687400 (AF035824) vesicle soluble NSF attachment protein receptor 1.00E−23 [Homo sapiens] 730 2914385 Chain C, Human Pcna > gi|2914387|pdb|1AXC|E Chain E, 2.00E−27 Human Pcna 731 284076 ERD-2-like protein, ELP-1-human 1.00E−26 733 2497524 KINESIN-LIKE PROTEIN KIF1B mouse > 9.00E−33 gi|407339|dbj|BAA04503| (D17577) Kif1b [Mus musculus] 735 3327056 (AB014521) KIAA0621 protein [Homo sapiens] 1.00E−13 736 279567 insulinase (EC 3.4.99.45)-human 2.00E−26 738 487416 (L20302) actin filament protein [Gallus gallus] 3.00E−45 739 1731428 ZINC FINGER PROTEIN ZFP-38 7.00E−35 740 968973 (U29156) involved in signaling by the epidermal growth 1.00E−22 factor receptor; Method: conceptual translation supplied by author. [Mus musculus] (Y08135) acid sphingomyelinase-like phosphodiesterase [Mus 741 1552350 musculus] 2.00E−35 742 3327098 (AB014542) KIAA0642 protein [Homo sapiens] 3.00E−15 743 3914801 DNA-DIRECTED RNA POLYMERASE I 135 KD 2.00E−45 POLYPEPTIDE (RNA POLYMERASE I SUBUNIT 2) (RPA135) (RNA POLYMERASE I 127 KD SUBUNIT) > gi|2739048 (AF025424) RNA polymerase I 127 kDa subunit [Rattus norvegicus] 745 4165018 (D89053) Acyl-CoA synthetase 3 [Homo sapiens] 2.00E−53 746 968973 (U29156) involved in signaling by the epidermal growth 3.00E−40 factor receptor; Method: conceptual translation supplied by author. [Mus musculus] 747 4519883 (AB017970) dipeptidyl peptidase III 4.00E−50 748 3327052 (AB014519) KIAA0619 protein [Homo sapiens] 7.00E−30 749 538413 (L36315) zinc finger protein [Mus musculus] 6.00E−55 750 1717793 PROTEIN TSG24 (MEIOTIC CHECK POINT 1.00E−50 REGULATOR) > gi|1083553|pir∥A55117 tsg24 protein- mouse 751 3420277 (AF064826) glypican 4 [Homo sapiens] 3.00E−54 808 4580645 (AF118855) trans-prenyltransferase [Mus musculus] 2.00E−48 829 3882171 (AB018268) KIAA0725 protein [Homo sapiens] 3.00E−24 833 4104976 (AF043117) ubiquitin-fusion degradation protein 2 [Homo 2.00E−41 sapiens] 841 3242214 (AJ006778) DRIM protein [Homo sapiens] 4.00E−34 914 4191810 (AB006532) DNA helicase [Homo sapiens] 5.00E−41 959 3043714 (AB011167) KIAA0595 protein [Homo sapiens] 5.00E−20 982 4379097 (Y17999) Dyrk1B protein kinase [Homo sapiens] 3.00E−21 1028 3043712 (AB011166) KIAA0594 protein [Homo sapiens] 2.00E−49 1079 4240227 (AB020676) KIAA0869 protein [Homo sapiens] 4.00E−35 1091 4235226 (AF061025) leucine zipper-EF-hand containing 6.00E−34 transmembrane protein 1 [Homo sapiens] 1134 3426268 (AF044201) neural membrane protein 35; NMP35 [Rattus 1.00E−29 norvegicus] 1152 4507367 threonyl-tRNA synthetase SYNTHETASE, CYTOPLASMIC 3.00E−26 (THREONINE--TRNA LIGASE) (THRRS) 6.1.1.3)-human > gi|1464742 (M63180) threonyl-tRNA synthetase [Homo sapiens] 1153 2072294 (U95097) mitotic phosphoprotein 43 [Xenopus laevis] 1.00E−19 1163 543222 glutamine (Q)-rich factor 1, QRF-1-mouse factor 1, QRF-1 1.00E−39 [mice, B-cell leukemia, BCL1, Peptide Partial, 84 aa] (AF072759) fatty acid transport protein 4; FATP4 [Mus 1164 3335569 musculus] 7.00E−39 1168 2996194 (AF053232) SIK similar protein [Mus musculus] 1.00E−31 1172 2935597 (AC004262) R29368_2 [Homo sapiens] 6.00E−49 1201 2645205 (U63648) p160 myb-binding protein [Mus musculus] 1.00E−21 1204 1407655 (U58884) SH3P7 [Mus musculus] 8.00E−21 1214 2134381 polybromo 1 protein-chicken 8.00E−29 1219 4505613 PRKC, apoptosis, WT1, regulator par-4 [Homo sapiens] 6.00E−34 1229 3757892 (AF079765) enhancer of polycomb [Mus musculus] 3.00E−41 1231 2134436 zinc finger protein-chicken (fragment) 4.00E−37 1232 2393722 (U90313) glutathione-S-transferase homolog [Homo sapiens] 6.00E−34 1234 459002 (U00036) R151.6 gene product [Caenorhabditis elegans] 7.00E−10 1236 119530 PROTEIN DISULFIDE ISOMERASE-RELATED PROTEIN 3.00E−23 PRECURSOR (ERP72) > gi|87320|pir∥A23723 protein disulfide-isomerase (EC 5.3.4.1) ERp72 precursor-human protein [Homo sapiens] 1239 2073541 (L19437) transaldolase [Homo sapiens] > gi|2612879 2.00E−24 1241 984125 (X90857)-14 [Homo sapiens] 2.00E−23 1245 4106818 (AF083395) phospholipase A2-activating protein [Homo 4.00E−36 sapiens] 1247 4507955 YY1 transcription factor REPRESSOR PROTEIN YY1 (YIN 4.00E−27 AND YANG 1) (YY-1) (DELTA TRANSCRIPTION FACTOR) (NF-E1) > gi|38011|emb|CAA78455| 1250 1698779 (U70372) PAM COOH-terminal interactor protein 2 [Rattus 6.00E−35 norvegicus] 1252 4204684 (AF102542) beta-1,6-N-acetylglucosaminyltransferase core 9.00E−43 2/core 4 beta-1,6-N-acetylglucosaminyltransferase; core 2/4- GnT [Homo sapiens] 1255 2239126 (Y10746) methyl-CpG binding protein [Homo sapiens] 4.00E−16 1259 1747519 (U76759) nuclear protein NIP45 [Mus musculus] 2.00E−29 1260 545790 DARPP-32 = dopamine and cAMP-regulated phosphoprotein 1.00E−29 [human, brain, Peptide, 204 aa] sapiens] 1261 1709689 PEPTIDE METHIONINE SULFOXIDE REDUCTASE 1.00E−37 (PEPTIDE MET(O) REDUCTASE) > gi|1205993 taurus] 1265 2736151 (AF021935) mytonic dystrophy kinase-related Cdc42-binding 1.00E−41 kinase [Rattus norvegicus] 1267 3329392 (AF038961) SL15 protein [Homo sapiens] 8.00E−36 1268 4097712 (U67322) HBV associated factor [Homo sapiens] 7.00E−56 ELONGATION FACTOR G, MITOCHONDRIAL 1269 585084 PRECURSOR (MEF-G) > gi|543383|pir∥S40780 translation 7.00E−49 elongation factor G, mitochondrial-rat > gi|310102 1270 1438534 (U49057) rA9 [Rattus norvegicus] 3.00E−45 1271 1336628 (U57368) EGF repeat transmembrane protein [Mus musculus] 7.00E−47 1272 3914802 DNA-DIRECTED RNA POLYMERASE I LARGEST 1.00E−37 SUBUNIT (RNA POLYMERASE I 194 KD SUBUNIT) (RPA194) 1273 3387977 (AF070598) ABC transporter [Homo sapiens] 5.00E−50 1274 1717793 PROTEIN TSG24 (MEIOTIC CHECK POINT 2.00E−48 REGULATOR) > gi|1083553|pir∥A55117 tsg24 protein- mouse 1275 2493735 SKD3 PROTEIN SKD3 [Mus musculus] 7.00E−43 1276 1041038 (D78020) NFI-A4 [Rattus norvegicus] 3.00E−26 1284 4455118 (AF125158) zinc finger DNA binding protein 99 9.00E−41 1322 4049922 (AF072810) transcription factor WSTF [Homo sapiens] 4.00E−48 1338 4586287 (AB004794) DUF140 [Xenopus laevis] 3.00E−45 1345 3435244 (AF083322) centriole associated protein CEP110 [Homo 2.00E−40 sapiens] 1370 3413886 (AB007931) KIAA0462 protein [Homo sapiens] 2.00E−35 1462 3882311 (AB018338) KIAA0795 protein [Homo sapiens] 4.00E−47 1497 4240167 (AB020646) KIAA0839 protein [Homo sapiens] 2.00E−46 1517 4191610 (AF117107) IGF-II mRNA-binding protein 2 [Homo sapiens] 3.00E−49 1519 3135669 (AF064084) prenylcysteine carboxyl methyltransferase 1.00E−39 1529 3043548 (AB011084) KIAA0512 protein [Homo sapiens] 2.00E−47 1531 3093476 (AF008915) EVI-5 homolog [Homo sapiens] 6.00E−19 1532 3834629 (AF094519) diaphanous-related formin; p134 mDia2 [Mus 1.00E−32 musculus] 1533 3193226 (AF068706) gamma2-adaptin [Homo sapiens] 1.00E−46 1534 3851584 (AF092563) chromosome-associated protein-E [Homo 4.00E−48 sapiens] 1535 4101695 (AF006010) progestin induced protein [Homo sapiens] 5.00E−30 1550 3850704 (AJ005273) Kin17 [Homo sapiens] 9.00E−24 1553 4240147 (AB020636) KIAA0829 protein [Homo sapiens] 9.00E−41 1554 2137490 lymphocyte specific helicase-mouse musculus] 5.00E−35 1561 3327052 (AB014519) KIAA0619 protein [Homo sapiens] 1.00E−41 1563 2137494 M-sema F protein precusor-mouse F [mice, neonatal brain, 7.00E−34 Peptide, 834 aa] [Mus sp.] nuclear receptor co-repressor N-CoR-mouse musculus] 1564 2137603 > gi|1583865|prf∥12121436A thyroid hormone receptor co- 9.00E−41 repressor [Mus musculus] 1565 2674107 (AF023451) guanine nucleotide-exchange protein [Bos taurus] 3.00E−48 1587 3659505 (AC005084) similar to mouse mCASK-A; similar to 1.00E−57 e1288039 1649 114762 NUCLEOPHOSMIN (NPM) (NUCLEOLAR 6.00E−35 PHOSPHOPROTEIN B23) (NUMATRIN) (NUCLEOLAR PROTEIN NO38) sapiens] 1651 3327056 (AB014521) KIAA0621 protein [Homo sapiens] 8.00E−40 1688 4545264 (AF118240) peroxisomal biogenesis factor 16 [Homo sapiens] 2.00E−65 1694 2498864 RRP5 PROTEIN HOMOLOG (KIAA0185) hypothetical 7.00E−77 protein YM9959.11C of S.cerevisiae. [Homo sapiens] 1758 3420277 (AF064826) glypican 4 [Homo sapiens] 4.00E−76 1768 3088575 (AF059531) protein arginine N-methyltransferase 3 [Homo 7.00E−97 sapiens] 1771 4050034 (AF098482) transcriptional coactivator p52 [Homo sapiens] 2.00E−58 1811 4506357 UNKNOWN; PZR > gi|3851145 sapiens] 2.00E−60 1830 3387977 (AF070598) ABC transporter [Homo sapiens] e-113 1836 1709974 60S RIBOSOMAL PROTEIN L10A protein L10a [Rattus e-111 norvegicus] Ribosomal Protein RPL10A) [Homo sapiens] 1838 4507709 tissue specific transplantation antigen P35B > gi|1381179 9.00E−90 (U58766) FX [Homo sapiens] 1876 1117791 (U18297) MST1 [Homo sapiens] 4E−85 1877 4507015 copper transporter 1 3.00E−72 1897 4503301 2,4-dienoyl CoA reductase REDUCTASE, 6E−94 MITOCHONDRIAL PRECURSOR (2,4-DIENOYL-COA REDUCTASE (NADPH)) (4-ENOYL-COA REDUCTASE (NADPH)) precursor, mitochondrial-human > gi|602703 (L26050) 2,4-dienoyl-CoA reductase [Homo sapiens] > gi|2673979 precursor [Homo sapiens] > gi|4126313 (AF049895) 2,4-dienoyl-CoA reductase [Homo sapiens] 1901 126743 MICROTUBULE-ASSOCIATED PROTEIN 4 human > 6E−84 gi|187383 (M64571) microtubule-associated protein 4 [Homo sapiens] 1914 4505987 PTPRF interacting protein, binding protein 1 (liprin beta 1) > 4E−89 gi|3309539 (AF034802) liprin-beta1 [Homo sapiens] 1920 3043644 (AB011132) KIAA0560 protein [Homo sapiens] e-108 1944 3413892 (AB007934) KIAA0465 protein [Homo sapiens] 7.00E−87 1956 4185796 (AF103796) placenta-specific ATP-binding cassette 2E−68 transporter [Homo sapiens] 1973 4507145 UNKNOWN > gi|3873216 (AF065485) sorting nexin 4 [Homo 1.00E−73 sapiens] 2008 1083566 zinc finger protein/transactivator Zfp-38-mouse > gi|55477 2E−64 |emb| CAA45280| (X63747) Zfp-38 [Mus musculus] 2018 1806134 (Z67747) zinc finger protein [Mus musculus] 7.00E−78 2032 730451 60S RIBOSOMAL PROTEIN L13A (23 KD HIGHLY BASIC 4.00E−87 PROTEIN) > gi|345897|pir∥S29539 basic protein, 23K- human > gi|23691|emb|CAA40254| (X56932) 23 kD highly basic protein [Homo sapiens] 2285 4102967 (AF023142) pre-mRNA splicing SR protein rA4 [Homo 1.00E−33 sapiens] 2317 3108093 (AF061258) LIM protein [Homo sapiens] 6.00E−82 2318 3170887 (AF061555) ubiquitin-protein ligase E3-alpha [Mus musculus] e-104 2324 1552350 (Y08135) acid sphingomyelinase-like phosphodiesterase [Mus 6.00E−91 musculus] 2365 1552350 (Y08135) acid sphingomyelinase-like phosphodiesterase [Mus e-106 musculus] 2366 3242214 (AJ006778) DRIM protein [Homo sapiens] e-114 2387 4514653 (AB024057) vascular Rab-GAP/TBC-containing protein e-121 [Homo sapiens] 2441 2443367 (AB005216) Nck, Ash and phospholipase C gamma-binding e-120 protein NAP4 [Homo sapiens] 2475 119110 EBNA-1 NUCLEAR PROTEIN herpesvirus 4 (strain B95-8) > 2.00E−38 gi|1334880|emb|CAA24816.1| gene. [Human herpesvirus 4] 2479 121640 GLYCINE-RICH CELL WALL STRUCTURAL PROTEIN 8.00E−31 PRECURSOR > gi|72320|pir∥KNMU glycine-rich cell wall protein precursor-Arabidopsis thaliana 2495 1362077 glycin-rich protein-cowpea (fragment) 2E−40 2519 121640 GLYCINE-RICH CELL WALL STRUCTURAL PROTEIN 9.00E−27 PRECURSOR > gi|72320|pir∥KNMU glycine-rich cell wall protein precursor-Arabidopsis thaliana 2546 2674107 (AF023451) guanine nucleotide-exchange protein [Bos taurus] 5E−89 2548 3717978 (Y12431) 5S ribosomal protein [Mus musculus] 5E−94 2556 4191610 (AF117107) IGF-II mRNA-binding protein 2 [Homo sapiens] e-111 2578 2119281 CHO1 antigen-Chinese hamster e-101 2579 3435244 (AF083322) centriole associated protein CEP110 [Homo 2E−70 sapiens] 2591 1843434 (D88687) KM-102-derived reductase-like factor [Homo 4.00E−91 sapiens] 2604 3834629 (AF094519) diaphanous-related formin; p134 mDia2 [Mus 1E−49 musculus]

TABLE 3A Profile Hits SEQ ID NO: Description Start Stop Dir 1967 14_3_3 proteins 166 845 for 2366 3′5′-cyclic nucleotide phosphodiesterases 64 573 for 1579 4 transmembrane integral membrane proteins 300 924 rev 1978 4 transmembrane integral membrane proteins 340 941 rev 1652 7 transmembrane receptor (rhodopsin family) 109 647 rev 1927 7 transmembrane receptor (rhodopsin family) 84 947 rev 2068 7 transmembrane receptor (rhodopsin family) 305 975 for 1598 7 transmembrane receptor (Secretin family) 50 1269 for 1719 7 transmembrane receptor (Secretin family) 63 1160 rev 1911 7 trausmembrane receptor (Secretin family) 38 869 rev 1927 7 transmembrane receptor (Secretin family) 237 930 rev 2068 7 transmembrane receptor (Secretin family) 188 975 for 2341 7 transmembrane receptor (Secretin family) 377 1524 rev 1671 ATPases Associated with Various Cellular 136 718 for Activities 1672 ATPases Associated with Various Cellular 271 765 for Activities 1688 ATPases Associated with Various Cellular 206 709 rev Activities 1796 ATPases Associated with Various Cellular 139 783 for Activities 1830 ATPases Associated with Various Cellular 265 713 for Activities 1872 ATPases Associated with Various Cellular 152 616 rev Activities 1913 ATPases Associated with Various Cellular 12 510 for Activities 1922 ATPases Associated with Various Cellular 125 658 for Activities 1964 ATPases Associated with Various Cellular 97 752 for Activities 1997 ATPases Associated with Various Cellular 185 664 for Activities 2032 ATPases Associated with Various Cellular 69 485 for Activities 2170 ATPases Associated with Various Cellular 73 550 for Activities 2177 ATPases Associated with Various Cellular 340 928 for Activities 2290 ATPases Associated with Various Cellular 872 1390 rev Activities 2343 ATPases Associated with Various Cellular 122 635 for Activities 2358 ATPases Associated with Various Cellular 84 492 rev Activities 2390 ATPases Associated with Various Cellular 31 434 rev Activities 2414 ATPases Associated with Various Cellular 953 1358 rev Activities 2461 ATPases Associated with Various Cellular 192 690 rev Activities 2476 ATPases Associated with Various Cellular 51 593 for Activities 2482 ATPases Associated with Various Cellular 135 615 rev Activities 2578 ATPases Associated with Various Cellular 0 673 for Activities 1623 Basic region plus leucine zipper transcription 81 277 for factors 1715 C2 domain (prot. kinase C like) 403 582 for 2426 C2 domain (prot. kinase C like) 493 637 for 2238 Cysteine proteases 359 984 rev 1630 DEAD and DEAH box helicases 34 690 rev 1865 DEAD and DEAH box helicases 43 753 for 2517 DEAD and DEAH box helicases 426 719 for 1714 Dual specificity phosphatase, catalytic domain 365 696 rev 1728 Dual specificity phosphatase, catalytic domain 243 597 for 2087 Dual specificity phosphatase, catalytic domain 786 1566 for 1595 EF-hand 556 630 for 1671 Eukaryotic aspartyl proteases 116 763 for 1778 Eukaryotic aspartyl proteases 92 1008 rev 1903 Eukaryotic aspartyl proteases 73 603 rev 1945 Eukaryotic aspartyl proteases 147 694 rev 1963 Eukaryotic aspartyl proteases 38 740 rev 1991 Eukaryotic aspartyl proteases 404 1113 rev 2130 Eukaryotic aspartyl proteases 237 829 rev 2138 Eukaryotic aspartyl proteases 117 729 rev 2193 Eukaryotic aspartyl proteases 217 1397 rev 2290 Eukaryotic aspartyl proteases 413 1366 rev 2291 Eukaryotic aspartyl proteases 8 710 rev 2348 Eukaryotic aspartyl proteases 291 1146 rev 2430 Eukaryotic aspartyl proteases 216 1158 rev 2496 Eukaryotic aspartyl proteases 228 659 for 2523 Eukaryotic aspartyl proteases 276 1291 rev 2589 Eukaryotic aspartyl proteases 525 1431 for 1968 Fibronectin type II domain 455 565 rev 1779 G-protein alpha subunit 24 583 rev 1621 Helicases conserved C-terminal domain 160 309 for 1652 Helicases conserved C-terminal domain 363 560 rev 2192 Helix-loop-helix DNA binding domain 224 382 for 2181 kinase domain of tors 474 713 for 1825 mkk like kinases 17 626 rev 1876 mkk like kinases 35 719 for 2039 mkk like kinases 114 527 for 2526 mkk like kinases 9 463 for 1782 Neurotransmitter-gated ion-channel 267 1411 for 1922 Neurotransmitter-gated ion-channel 367 1168 for 2068 Neurotransmitter-gated ion-channel 222 1024 for 2102 Neurotransmitter-gated ion-channel 352 1273 for 2154 Neurotransmitter-gated ion-channel 377 1159 for 2538 Neurotransmitter-gated ion-channel 112 1120 for 1621 protein kinase 153 743 for 1630 protein kinase 123 904 for 1705 protein kinase 471 1072 for 1706 protein kinase 190 609 for 1710 protein kinase 235 641 for 1744 protein kinase 8 711 rev 1767 protein kinase 90 537 for 1776 protein kinase 200 524 rev 1782 protein kinase 706 1331 for 1822 protein kinase 24 666 for 1825 protein kinase 56 593 rev 1844 protein kinase 263 824 for 1850 protein kinase 217 779 for 1876 protein kinase 290 711 for 1977 protein kinase 38 776 for 2051 protein kinase 14 657 for 2112 protein kinase 202 644 rev 2169 protein kinase 1 656 for 2205 protein kinase 57 689 for 2242 protein kinase 33 646 for 2291 protein kinase 630 1148 rev 2454 protein kinase 49 761 rev 2526 protein kinase 0 463 for 2558 protein kinase 77 590 for 1719 Protein Tyrosine Phosphatase 82 482 rev 1769 Protein Tyrosine Phosphatase 71 461 rev 2062 Protein Tyrosine Phosphatase 270 704 for 2197 Protein Tyrosine Phosphatase 359 851 for 2275 Protein Tyrosine Phosphatase 56 680 for 1850 RNA recognition motif. (aka RRM, RBD, or 165 365 for RNP domain) 2194 RNA recognition motif. (aka RRM, RBD, or 37 174 for RNP domain) 2441 SH2 Domain 201 362 for 1618 Thioredoxins 253 554 for 1579 Trypsin 252 1007 rev 2290 Trypsin 350 1164 rev 2341 Trypsin 447 1211 rev 2421 Trypsin 14 765 rev 2430 Trypsin 700 1556 rev 2438 Trypsin 47 670 rev 2281 WD domain, G-beta repeats 70 161 for 1579 wnt family of developmental signaling proteins 282 1017 rev 1653 wnt family of developmental signaling proteins 154 978 rev 1778 wnt family of developmental signaling proteins 38 858 rev 1826 wnt family of developmental signaling proteins 574 1318 rev 1875 wnt family of developmental signaling proteins 578 1313 rev 1904 wnt family of developmental signaling proteins 205 1068 rev 1992 wnt family of developmental signaling proteins 2 824 rev 2004 wnt family of developmental signaling proteins 621 1420 rev 2129 wnt family of developmental signaling proteins 394 1343 rev 2145 wnt family of developmental signaling proteins 162 1027 rev 2204 wnt family of developmental signaling proteins 274 1405 rev 2238 wnt family of developmental signaling proteins 560 1195 rev 2290 wnt family of developmental signaling proteins 250 1273 rev 2291 wnt family of developmental signaling proteins 523 1409 rev 2294 wnt family of developmental signaling proteins 297 1237 rev 2341 wnt family of developmental signaling proteins 51 1002 rev 2343 wnt family of developmental signaling proteins 28 1180 rev 2348 wnt family of developmental signaling proteins 638 1614 rev 2373 wnt family of developmental signaling proteins 30 1078 rev 2409 wnt family of developmental signaling proteins 4 1074 rev 2410 wnt family of developmental signaling proteins 208 1107 rev 2414 wnt family of developmental signaling proteins 242 1068 rev 2421 wnt family of developmental signaling proteins 159 1057 rev 2430 wnt family of developmental signaling proteins 844 1691 rev 2436 wnt family of developmental signaling proteins 107 784 rev 2438 wnt family of developmental signaling proteins 127 1226 rev 2463 wnt family of developmental signaling proteins 5 704 rev 2473 wnt family of developmental signaling proteins 328 1193 rev 2511 wnt family of developmental signaling proteins 341 1222 rev 2523 wnt family of developmental signaling proteins 820 1617 rev 2528 wnt family of developmental signaling proteins 461 1283 rev 1735 Zinc finger, C2H2 type 495 557 for 1942 Zinc finger, C2H2 type 500 562 for 2018 Zinc finger, C2H2 type 279 341 for 2254 Zinc finger, C2H2 type 148 210 for 2515 Zinc finger, C2H2 type 422 484 for

TABLE 3B Profile Hits for Contigs SEQ ID NO: Description Start Stop Dir 2641 ATPases Associated with Various Cellular 118 661 for Activities 2655 ATPases Associated with Various Cellular 135 536 for Activities 2685 ATPases Associated with Various Cellular 142 574 for Activities 2648 DEAD and DEAH box helicases 66 931 rev 2686 Helicases conserved C-terminal domain 51 242 for 2661 Neurotransmitter-gated ion-channel 169 738 rev 2640 Protein phosphatase 2A regulatory subunit 275 1510 for PR55 2655 Protein phosphatase 2A regulatory subunit 55 1087 for PR55 2670 Protein phosphatase 2A regulatory subunit 13 1183 for PR55 2684 Protein phosphatase 2A regulatory subunit 511 1861 rev PR55 2679 Protein Tyrosine Phosphatase 292 768 for 2668 Thioredoxins 182 475 for

TABLE 22 Deposits of Pooled Clones ES34 ES35 ES36 ES37 M00006992C:G02 M00005468A:D08 M00005452C:A02 M00022171D:B08 M00006756D:E10 M00021892B:H03 M00001382C:C09 M00008061A:F02 M00003984C:F04 M00001390A:C06 M00004841C:B09 M00003820C:A09 M00007125D:E03 M00022074D:F11 M00001441D:H05 M00022109B:A11 M00006650A:A10 M00005460B:D02 M00022716D:D08 M00005342D:F03 M00001452B:H06 M00022423B:D03 M00022828C:E04 M00022070B:C10 M00022972D:C10 M00007140A:F11 M00004350B:F06 M00006966B:B09 M00022305C:A01 M00004081B:C11 M00005685B:D08 M00022381C:C12 M00007010B:H01 M00005480A:H12 M00004190A:A09 M00003991B:B05 M00021946D:C11 M00008015D:E09 M00004054D:D02 M00022404D:G05 ES38 ES39 ES40 ES41 M00021912B:H11 M00007118B:B04 M00006993B:B09 M00007974B:C11 M00005378C:A10 M00007019A:B01 M00004242C:C01 M00021860B:G06 M00022578C:B07 M00021682B:D12 M00007986C:C05 M00006927C:F12 M00005513A:D08 M00005411D:A03 M00004115A:G09 M00022582C:E12 M00022176C:A08 M00006641C:H02 M00022600C:A06 M00006618C:G08 M00006822D:F07 M00007041B:C05 M00005384A:A01 M00005450B:B01 M00004031A:B04 M00005444B:E11 M00021667D:E03 M00001417B:E01 M00021927D:D12 M00022745B:G02 M00008078C:C06 M00003825B:A05 M00001553D:B06 M00022685A:F11 M00007985A:B09 M00001370B:B04 M00022404B:H05 M00004446A:G01 M00007953B:B03 M00006727B:E09 ES42 ES43 ES44 ES45 M00001478A:B06 M00006923B:H08 M00006615B:F05 M00005468D:F04 M00003972B:A11 M00005377D:F11 M00005486C:B03 M00006720C:C11 M00005477C:D08 M00006640B:H09 M00007124C:A11 M00005817D:E12 M00006745A:A01 M00005404C:F02 M00006995D:A03 M00001669B:A03 M00007090B:A02 M00004030A:G12 M00007149D:G06 M00003998A:G12 M00007152A:B04 M00006704D:D03 M00006990D:D06 M00004045A:B12 M00006953B:H10 M00006810D:A05 M00005530B:E04 M00004130D:E04 M00005399D:B02 M00005481C:A05 M00003918C:E07 M00004160A:D07 M00006987B:F04 M00005411A:C07 M00007163A:B10 M00001655A:F07 M00005772A:F03 M00003970A:G10 M00005485C:A03 M00001468D:D11 ES46 M00004217A:A05 M00004183D:B07 M00001415D:A05 M00004158C:F03 M00004031D:G02

TABLE 23 Library Deposits ES47 ES48 ES49 ES50 M00001399D:F09 M00004217D:G10 M00004508A:G12 M00021653A:G07 M00001455A:C03 M00004218C:G10 M00004508B:G02 M00021654C:A02 M00001456C:F02 M00004252D:H08 M00001432B:H08 M00021660C:G04 M00001487D:G03 M00004253B:A10 M00001432C:G01 M00021665A:D04 M00001539B:B01 M00004253B:F06 M00003992D:G01 M00021670B:G11 M00001565A:A02 M00004253C:E10 M00005326B:F03 M00021678A:B08 M00001572C:E07 M00004260A:B07 M00005332A:H10 M00021680B:C01 M00001582D:B10 M00004260C:A12 M00005342A:C04 M00021681C:B10 M00001584C:A03 M00004260C:E10 M00005342A:D04 M00021690D:E05 M00001586A:F09 M00001339B:A03 M00005349B:G01 M00021692A:E03 M00001588D:H08 M00001342C:A04 M00005352B:D02 M00021692C:E06 M00001610B:A01 M00001344D:G11 M00005354C:E02 M00021694B:A07 M00001618B:F02 M00001345A:A12 M00005356A:D09 M00021698B:B12 M00001618C:E06 M00001347A:G06 M00005359D:G07 M00021828A:C08 M00001621C:A04 M00001347B:H01 M00005378A:A08 M00021841C:D07 M00001626B:H05 M00001353B:D11 M00005383D:D06 M00021859A:D04 M00001641B:G05 M00001355B:A01 M00005383D:E07 M00021861C:A02 M00001648C:F06 M00001358D:D09 M00005385C:G05 M00021862A:A04 M00001649D:H05 M00001359A:B07 M00005388D:F09 M00021862D:F01 M00001656D:F11 M00001362A:C10 M00005390B:G10 M00021886D:E04 M00001660A:F10 M00001362B:A09 M00005397C:B03 M00021897B:A06 M00001669A:H11 M00001365D:D12 M00005399A:D01 M00021905A:G05 M00003741A:E01 M00001365D:H09 M00005409D:C02 M00021905B:A01 M00003745C:E03 M00001370A:G09 M00005415C:G08 M00021906C:G11 M00003746A:E01 M00001370B:B12 M00005417A:E10 M00021910A:C10 M00003748B:B06 M00001374D:D09 M00005442D:C05 M00021927A:C11 M00003749B:C08 M00001376B:C11 M00005446A:G01 M00021927B:F01 M00003749D:G07 M00001377A:D03 M00005446C:D12 M00021932C:C05 M00003752A:B06 M00001377A:E01 M00005454C:H12 M00021932C:G10 M00003752D:D09 M00001377C:B08 M00005455A:D01 M00021947A:C01 M00003753C:B01 M00001387A:A04 M00005455A:G03 M00021952B:F11 M00003754C:F01 M00001387D:C07 M00005462C:B02 M00021954A:A03 M00003756C:C08 M00001389B:B06 M00005469D:C11 M00021964A:C04 M00003759A:E10 M00001390A:H01 M00005480C:B12 M00021967D:E08 M00003762A:D11 M00001399C:E10 M00005483D:A12 M00021977D:E02 M00003763B:D03 M00001401D:D04 M00005484A:D09 M00021978A:F08 M00003763D:F06 M00001402D:C07 M00005491B:C03 M00021982C:F08 M00003765D:E02 M00001402D:H03 M00005493B:C08 M00021983B:B03 M00003766B:G04 M00001403B:A01 M00005494D:F11 M00021983D:B10 M00003767C:F04 M00001405D:F05 M00005496C:A01 M00022005C:G03 M00003769B:A04 M00001406C:A11 M00005496D:A10 M00022032A:E07 M00003769D:G12 M00001406D:H01 M00005497B:H07 M00022049A:A02 M00003770D:C07 M00001407B:A08 M00005497C:C07 M00022049A:D06 M00003771A:G09 M00001407D:H11 M00005497C:C12 M00022054D:C05 M00003771D:A10 M00001411A:D01 M00005497C:E03 M00022064C:H07 M00003773A:C09 M00001411C:G02 M00005498B:F08 M00022067D:C05 M00003773B:E09 M00001412A:A11 M00005498C:G05 M00022068B:H11 M00003773B:G08 M00001415D:E12 M00005508B:B04 M00022068D:D12 M00003773C:G06 M00001417C:E02 M00005524C:B01 M00022069D:G02 M00003773D:C02 M00001421A:H07 M00005528D:A10 M00022071B:D05 M00003789C:E03 M00001422D:D02 M00005530B:D03 M00022071C:D09 M00003790B:F12 M00001423C:D06 M00005534B:H10 M00022075D:F05 M00003793C:D11 M00001424A:H09 M00005548B:E03 M00022081C:G11 M00003796B:C07 M00001425C:E10 M00005550B:D09 M00022084B:F04 M00003797D:H06 M00001426A:F09 M00005565C:A08 M00022085C:C04 M00003801D:F05 M00001426D:D09 M00005589C:B03 M00022090A:G08 M00003805A:G05 M00001431A:C10 M00005616B:D05 M00022093A:A05 M00003808C:D09 M00001431A:E05 M00005620C:C05 M00022093D:B10 M00003809A:A12 M00001432A:F12 M00005621A:G10 M00022094B:G10 M00003809A:H12 M00001432B:H08 M00005621D:F01 M00022106C:F04 M00003813D:A06 M00001432C:G01 M00005631A:A11 M00022110A:E04 M00003818A:F09 M00001433A:C07 M00005632C:D06 M00022114C:B02 M00003818B:A01 M00001434A:A01 M00005637B:D12 M00022117C:G07 M00003819D:G09 M00001435A:F03 M00005642B:C03 M00022128A:D04 M00003821C:E04 M00001435A:G01 M00005647D:D09 M00022139A:C01 M00003822A:G05 M00001435B:G10 M00005655B:C02 M00022149B:D05 M00003825C:B02 M00001435C:G08 M00005703A:C08 M00022150A:H06 M00003825C:B12 M00001435D:A06 M00005704A:B11 M00022153D:D11 M00003833B:A11 M00001436D:C10 M00005708D:B03 M00022157A:F12 M00003834A:A03 M00001437B:B05 M00005710A:C08 M00022157B:A10 M00003835D:H05 M00001438C:H05 M00005720A:D03 M00022169D:C02 M00003839D:G06 M00001439B:F10 M00005722D:G03 M00022170D:H09 M00003841A:E09 M00001439C:A01 M00005743B:F02 M00022175A:A11 M00003841B:D05 M00001439C:G06 M00005763B:H09 M00022176A:E08 M00003843A:B01 M00001442A:D08 M00005765C:C04 M00022178D:H01 M00003844C:D04 M00001443D:A01 M00005810C:D04 M00022183A:G03 M00003844C:H05 M00001444A:A09 M00005813D:F06 M00022189A:A01 M00003846B:H02 M00001446D:B10 M00005818C:E08 M00022198A:C12 M00003850B:D11 M00001452D:E05 M00005818C:G01 M00022199C:F03 M00003852D:D03 M00001453D:F09 M00006576D:F11 M00022202C:F11 M00003859C:B09 M00001463C:A01 M00006577B:H12 M00022206B:G06 M00003868D:F02 M00001466C:F02 M00006587A:H08 M00022212C:C02 M00003868D:F07 M00001471C:G03 M00006594A:E08 M00022216D:C01 M00003871A:E09 M00001488B:G12 M00006596D:H04 M00022218C:B06 M00003884D:A12 M00001489B:F08 M00006601C:A07 M00022218D:B12 M00003887B:C03 M00001489D:C08 M00006601C:E06 M00022220C:F08 M00003888B:A10 M00001490B:G04 M00006609A:G10 M00022221D:E08 M00003888C:E01 M00001491C:C01 M00006633C:E11 M00022226C:B06 M00003890B:H07 M00001496A:B03 M00006633D:A06 M00022226D:A07 M00003890D:C03 M00001496D:D02 M00006634B:C02 M00022231A:F12 M00003892D:D04 M00001500A:D09 M00006636A:B08 M00022231C:A04 M00003893C:D12 M00001504D:D09 M00006644A:B11 M00022236D:A03 M00003895D:A03 M00001505A:E09 M00006644D:C02 M00022239A:A10 M00003896B:F08 M00001506A:F01 M00006686A:G12 M00022239B:B07 M00003896D:B01 M00001517D:C03 M00006692B:E04 M00022239D:A07 M00003903C:H03 M00001518D:A10 M00006728D:G10 M00022252C:E06 M00003905C:B01 M00001536B:B11 M00006733D:G12 M00022253B:E06 M00003905C:E10 M00001537B:C12 M00006734A:H12 M00022254C:D08 M00003906C:H12 M00001542C:D10 M00006735A:H02 M00022255A:C08 M00003909D:G01 M00001542C:F06 M00006764B:D05 M00022255D:E03 M00003911C:G05 M00001543A:E04 M00006765B:H06 M00022258C:F06 M00003912B:G11 M00001546B:H01 M00006785B:F09 M00022259B:G02 M00003912C:C11 M00001551D:C12 M00006791B:B08 M00022278C:E03 M00003914C:E03 M00001552B:D01 M00006796A:C03 M00022278D:F10 M00003915A:D09 M00001556D:A11 M00006800C:G08 M00022288C:D04 M00003915C:G01 M00001557C:B08 M00006814A:F07 M00022289A:D05 M00003920B:A10 M00001558B:A12 M00006819A:D10 M00022289D:B06 M00003921D:C06 M00001560C:C01 M00006820A:G05 M00022294A:D11 M00003923A:H07 M00001561B:C10 M00006821C:C10 M00022296B:C11 M00003936C:F10 M00001597C:B03 M00006822A:D07 M00022305A:H11 M00003948B:B03 M00001623B:B01 M00006823D:D12 M00022364C:G12 M00003949B:A08 M00001623D:A09 M00006826B:H03 M00022366B:E09 M00003949B:D05 M00001644D:F09 M00006828D:C12 M00022372B:D03 M00003961B:A12 M00003784C:B09 M00006832D:F11 M00022381A:F05 M00003961C:G02 M00003785D:E01 M00006846A:B01 M00022382D:H11 M00003962B:B09 M00003862C:H10 M00006850C:D09 M00022386A:A07 M00003963B:D12 M00003864B:A04 M00006850C:G07 M00022386B:D11 M00003973A:C05 M00003864D:G05 M00006851C:H09 M00022386C:A04 M00003973B:H06 M00003992C:G01 M00006863B:E06 M00022386C:D07 M00003976D:D12 M00003992D:G01 M00006866C:F03 M00022399C:A10 M00003977C:A08 M00003994C:C11 M00006867C:E07 M00022407C:H11 M00003980B:F12 M00003996D:C04 M00006868D:E02 M00022411D:G09 M00003980C:G10 M00003997D:D07 M00006870C:H06 M00022412A:C08 M00003981C:E04 M00003998A:D03 M00006873B:G11 M00022444A:A11 M00003983C:E07 M00003998C:H10 M00006875A:A02 M00022449C:B01 M00003987D:F06 M00003999C:C12 M00006877B:E05 M00022452C:B03 M00004027A:B10 M00004046A:F04 M00006879A:H11 M00022457C:B01 M00004027C:H01 M00004051C:D02 M00006882A:D01 M00022495C:G05 M00004028C:B04 M00004052C:A08 M00006901D:A11 M00022504B:E03 M00004030B:B02 M00004052C:B05 M00006907C:D03 M00022505D:A12 M00004030B:C05 M00004054B:G02 M00006907D:C07 M00022509D:F06 M00004035D:E04 M00004054D:A03 M00006912B:E01 M00022527A:E05 M00004036B:F09 M00004055B:F06 M00006921B:E01 M00022527D:B03 M00004036C:D01 M00004058B:C11 M00006960D:E06 M00022531B:D07 M00004037A:A07 M00004058C:E08 M00006963A:H11 M00022535D:B11 M00004037B:B05 M00004059A:G09 M00006966C:B07 M00022535D:C04 M00004038C:C05 M00004060C:A02 M00006972A:F10 M00022536B:B04 M00004038C:D12 M00004060D:A07 M00006973C:E11 M00022551A:G03 M00004039D:D03 M00004063C:B11 M00006973D:E11 M00022556B:C04 M00004040B:B09 M00004143A:G12 M00006974B:F06 M00022556B:G02 M00004040C:G12 M00004143A:H07 M00006976C:E09 M00022562C:H10 M00004040D:B05 M00004145C:A03 M00007014C:B07 M00022578B:G05 M00004041B:F01 M00004146D:A07 M00007015C:G05 M00022578D:F03 M00004041D:E06 M00004147A:G03 M00007016C:E06 M00022583B:E05 M00004043D:C10 M00004149B:H12 M00007041B:G01 M00022587C:G04 M00004069D:G02 M00004153D:E06 M00007042A:E07 M00022594B:H12 M00004071A:H03 M00004154D:F11 M00007043A:B05 M00022598A:F11 M00004073D:B11 M00004159D:C04 M00007046A:D02 M00022599D:E07 M00004076D:B03 M00004166B:E10 M00007047B:D01 M00022604B:C11 M00004081C:A01 M00004166C:A03 M00007051D:D09 M00022607B:A04 M00004084C:G04 M00004166D:G07 M00007053B:H03 M00022613D:C04 M00004085B:G06 M00004196C:G05 M00007058A:C02 M00022651D:C06 M00004087C:F05 M00004234B:E03 M00007062A:D03 M00022666C:H11 M00004091A:E01 M00004234B:G06 M00007099A:F09 M00022681C:H02 M00004091B:C12 M00004236D:E07 M00007100C:D01 M00022682A:F12 M00004091B:G04 M00004236D:F04 M00007112B:C06 M00022698C:E06 M00004091C:F04 M00004240D:A07 M00007105D:C07 M00022701B:B12 M00004091D:D09 M00004242C:C02 M00007121A:A05 M00022708A:C08 M00004092A:C03 M00004244B:A02 M00007122A:G11 M00022708D:G10 M00004092A:D04 M00004245A:G09 M00007122B:A11 M00022725C:E09 M00004093D:D09 M00004245C:A03 M00007127B:A04 M00022726A:A06 M00004101D:A03 M00004247A:E01 M00007129A:G10 M00022730A:E04 M00004103B:C07 M00004247B:C11 M00007130B:B03 M00022737A:C08 M00004107C:A01 M00004248A:G08 M00007132D:G08 M00022763A:E10 M00004114C:F02 M00004263D:F06 M00007134C:F07 M00022824C:H11 M00004115A:F01 M00004272D:D02 M00007137D:C10 M00022835C:E06 M00004117B:F01 M00004273D:E11 M00007140D:C12 M00022854D:H07 M00004120A:C02 M00004277D:C08 M00007150A:C09 M00022856A:D02 M00004126B:G02 M00004281B:B05 M00007150A:H06 M00022856B:F04 M00004129A:H08 M00004283C:D03 M00007154A:E04 M00022856C:B11 M00004130C:A09 M00004285B:E01 M00007163A:F11 M00022893C:H11 M00004133D:A01 M00004297D:E08 M00007163B:A12 M00022897A:F04 M00004178B:F06 M00004298B:D04 M00007166B:E06 M00022900D:E08 M00004180B:F04 M00004308A:E06 M00007170D:A10 M00022900D:G03 M00004184B:F11 M00004324B:D09 M00007172A:A05 M00004191B:G01 M00004328A:H06 M00007172D:C08 M00004193A:C07 M00004329C:F11 M00007188A:D03 M00004193C:H01 M00004331D:H08 M00007189D:A09 M00004199D:C02 M00004332C:E09 M00007193D:A04 M00004200A:A09 M00004337D:G08 M00007195B:B02 M00004200A:G06 M00004345A:H06 M00007198C:A10 M00004200D:A07 M00004383A:F02 M00007199D:B07 M00004201D:C11 M00004385C:B11 M00007204C:F09 M00004201D:E12 M00004388C:D05 M00007929B:H10 M00004202B:A02 M00004406A:H03 M00007961A:B01 M00004204A:D04 M00004408D:A10 M00007964B:D10 M00004204A:D10 M00004410A:E03 M00007971A:B04 M00004204B:A04 M00004412B:E03 M00007977C:E08 M00004210A:B09 M00004421A:G04 M00007995D:E06 M00004216D:E10 M00004447D:D10 M00008074D:C01 M00004217A:A11 M00004460B:H09 M00008094A:E10 M00004465C:B10 M00021611D:D05 M00004465C:B12 M00021611D:H03 M00004467A:F09 M00021614B:G12 M00004467D:F09 M00021618D:D07 M00004491D:D07 M00021624A:D07 M00004497C:E09 M00021624B:A03 M00004501A:G06 M00021625A:C07 M00004506C:H10 M00021629D:D05

TABLE 24 Library Deposits ES51 ES52 ES53 ES54 M00001448A:D05 M00001439B:E02 M00006621A:G10 M00021640A:G03 M00001458B:F06 M00001443A:E02 M00006626A:G11 M00021657B:C08 M00001530A:D11 M00001443D:C03 M00006629D:D04 M00021690B:B06 M00001563C:D06 M00001444A:G12 M00006630B:H06 M00021690C:B07 M00001564C:D04 M00001445B:E03 M00006631D:B02 M00022071C:C09 M00001569B:F04 M00001451B:H11 M00006631D:C04 M00022081C:B11 M00001575A:H02 M00001452B:F09 M00006631D:E09 M00022085C:A07 M00001589C:D12 M00001488B:H02 M00006635C:B10 M00022091B:B07 M00001589D:G10 M00001491D:E07 M00006636A:E06 M00022122D:D06 M00001590D:A07 M00001496C:H10 M00006636D:A05 M00022150D:D11 M00001598C:D10 M00001499A:D01 M00006636D:F11 M00022154A:C01 M00001599A:H09 M00001499A:D05 M00006640A:B01 M00022170D:H07 M00001609A:B12 M00001499B:H05 M00006640B:F05 M00022365A:A01 M00001614C:G04 M00001500B:H07 M00006640D:H08 M00022389B:H04 M00001626C:C10 M00001504C:H11 M00006641A:B03 M00022439A:E07 M00001634C:E12 M00001506D:A11 M00006643A:E10 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M00006619B:C11 M00007200B:C02 M00001438B:H06 M00021619B:G10 

1. An isolated polynucleotide comprising at least 150 contiguous nucleotides of a sequence selected from SEQ ID NO:972 and a complement of SEQ ID:972.
 2. A vector comprising a polynucleotide of claim
 1. 3. A host cell comprising the vector of claim
 2. 4. An isolated polynucleotide comprising at least 200 contiguous nucleotides of SEQ ID NO:972 and which hybridizes under stringent conditions to a polynucleotide of a sequence selected from SEQ ID NO:972 and a complement of SEQ ID:972.
 5. An isolated polynucleotide comprising a nucleotide sequence of an insert contained in a clone deposited as clone number M00007118B:B04 of ATCC Deposit Number PTA-60, wherein said isolated polynucleotide comprises at least 1.50 contiguous nucleotides of a sequence selected from SEQ ID NO:972 and a complement of SEQ ID NO:972.
 6. An isolated polynucleotide comprising at least 150 contiguous nucleotides of SEQ ID NO:972 obtained by amplifying a fragment of cDNA using at least one polynucleotide primer comprising at least 15 contiguous nucleotides of a nucleotide sequence selected from the group consisting of: SEQ ID NO: 972 and a complement of SEQ ID NO:
 972. 7. A vector comprising a polynucleotide of claim
 6. 8. A host cell comprising the vector of claim
 7. 